Clinical Features of Tubulointerstitial Nephritis and Uveitis (TINU) Syndrome in Hokkaido, Japan

Clinical Features of Tubulointerstitial Nephritis and Uveitis (TINU) Syndrome in Hokkaido, Japan | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical Features of Tubulointerstitial Nephritis and Uveitis (TINU) Syndrome in Hokkaido, Japan Takako Ito, Kenichi Namba, Daiju Iwata, Kazuomi Mizuuchi, Satoru Kase, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8535691/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose Although tubulointerstitial nephritis and uveitis (TINU) syndrome is considered to have a relatively good prognosis, its actual clinical features are not well understood. This study examined the clinical features of TINU syndrome cases that visited our hospital. Methods Patients who visited Hokkaido University Hospital and were diagnosed with TINU syndrome between 2004 and 2018 were included. Ocular findings, laboratory results, and treatment records were retrospectively reviewed from clinical charts. Results A total of 61 eyes from 31 patients were included: seven “definite” and 24 “probable” TINU cases. Age at first examination ranged from eight to 54 years (mean 16.0 years). Anterior uveitis was present in all eyes, while posterior segment inflammation was found in 79%, including vitreous haze, optic disc redness, dilated retinal vessels, retinal exudates, and serous retinal detachment. Urine β2-microglobulin was elevated in all patients, and serum soluble interleukin-2 receptor (sIL-2R) was elevated in 67%. Oral corticosteroids were required in 55% of patients, and recurrence occurred in 65%. Most cases achieved remission of uveitis by age 24. Final corrected visual acuity was 0.8 or better in 93% of patients, while 4% had 0.2 or worse. Conclusion More than three-quarters of cases showed not only anterior chamber inflammation but also posterior ocular inflammatory findings. Elevated sIL-2R was a reliable marker for TINU syndrome. Most cases achieved remission by adulthood and had a good visual prognosis, although some experienced poor outcomes due to ocular complications. tubulointerstitial nephritis and uveitis (TINU) syndrome β2-microglobulin soluble interleukin-2 receptor (sIL-2R) corticosteroids Figures Figure 1 Figure 2 Introduction Tubulointerstitial nephritis and uveitis (TINU) syndrome is a disorder characterized by idiopathic acute tubulointerstitial nephritis (AIN) accompanied with uveitis. It was first described by Dobrin et al. in 1975 [ 1 ]. The pathogenesis remains incompletely understood; however, it is thought to involve an immune reaction against shared antigens in the uvea and renal tubular cells [ 2 ]. TINU syndrome is often observed in adolescent females around the age of 15 [ 3 ] and is generally considered to have a relatively good prognosis, although reported outcomes vary [ 3 – 6 ]. We previously reported on patients with TINU syndrome who first visited our hospital between 1993 and 2003 [ 4 ]. This report summarizes the clinical features of patients who newly presented thereafter. Methods Ethics statement This study was approved by the Hokkaido University Institutional Review Board for Clinical Research (No. 019–0269). The tenets of the Declaration of Helsinki were followed, and the need for written informed consent was formally waived by the ethics committee. Subjects Newly diagnosed TINU syndrome cases at Hokkaido University Hospital between January 2004 and December 2018 who were followed for more than six months were included in this study. Diagnosis was confirmed by uveitis specialists based on criteria of Mandeville et al [ 3 ]. These require the presence of both AIN and uveitis, along with the exclusion of other known systemic diseases that could cause either condition. Cases are categorized as “definite,” “probable,” or “possible” depending on whether uveitis is typical or atypical and whether AIN diagnosis is histological or clinical. This study included “definite” and “probable” cases, while two “possible” cases were excluded. We retrospectively collected demographic information, age, disease duration, anatomical localization, laterality, mode of onset, uveitis complications, and treatments from patients’ medical records. Ocular findings were graded using the Standard Uveitis Nomenclature (SUN) criteria [ 7 ]. Recurrence was defined as ≥ 2 anterior chamber cells or newly observed posterior segment findings. Remission was defined as inactive uveitis for at least six months after discontinuation of treatment. Ocular hypertension was defined as an intraocular pressure exceeding 21 mmHg on two or more occasions. Results Patients’ characteristics Sixty-one eyes of 31 patients were included in this study. At first presentation, ages ranged from eight to 54 years (mean: 16.0 years), with 29 patients (93.5%) under 20 years old. Of these, 21 patients (67.7%) were female (Figure 1). Seven cases were classified as “definite” and 24 as “probable” TINU syndrome (Table 1). Uveitis was bilateral in 30 cases and unilateral in one. The follow-up period ranged from 12 to 188 months (mean: 94.8). None of the patients had suspected triggers such as infection, vaccination, or medication. Three patients were diagnosed with AIN before uveitis onset, while 28 were diagnosed concurrently with uveitis. No cases were diagnosed with AIN afterward. Ocular manifestations Ocular symptoms at onset are summarized in Table 2. The most common symptom was ocular redness (hyperemia) (71.0%), followed by blurred vision (32.3%) and ocular pain (29.0%). Ocular findings are shown in Table 3. Anterior segment involvement was present in all 61 eyes, while posterior segment findings were observed in 48 eyes (78.7%) (i.e., only anterior segment findings were seen in 21.3% of eyes). Severe iridocyclitis (≥ 3 anterior chamber cells) was present in 25 eyes (41.0%), and inflammatory iris rubeosis occurred in two eyes. Keratic precipitates were found in 37 eyes (60.7%), with mutton-fat keratic precipitates in 17 eyes (27.9%) (Fig. 2-A). Posterior synechia was seen in 22 eyes (36.1%). Iris nodules (Fig. 2-B) were found in nine eyes (14.8%) and trabecular meshwork nodules (Fig. 2-C) in 17 eyes (27.9%). Posterior segment findings included optic disc redness (36 eyes, 59.0%) and vitreous haze (34 eyes, 55.7%), with either present in 47 eyes (77.0%). Other findings included snowball vitreous opacities in 13 eyes (21.3%), dilated retinal vessels in six eyes (9.8%), and retinal exudates in nine eyes (14.8%). Fluorescein fundus angiography was performed in 14 eyes (7 patients). Optic disc hyperfluorescence was seen in six eyes (42.9%), leakage from retinal vessels in seven eyes (50.0%), and leakage from optic disc neovascularization (Fig. 2-E) in one eye (7.1%). Laboratory findings Urinalysis and blood tests were performed in all patients at the first visit to our hospital (Table 4). Urine β2 microglobulin (β2MG) was elevated in all patients with a mean value of 4.80 (normal range: 0.027–0.275 mg/L). In 20 cases, levels were more than five times the upper limit, and in 11 cases, they were more than 10 times the upper limit. Urine N-acetylglucosaminidase (NAG) levels were elevated in 12 of 29 cases (41.4%). Proteinuria and glucosuria were present in 18 cases (58.1%) and 11 cases (35.5%), respectively. Blood tests showed normal blood urea nitrogen in all patients. Serum creatinine (Cre) was slightly elevated (up to 1.6 mg/dL; normal range: 0.4–0.7 mg/dL in females and 0.4–1.1 mg/dL in males) in 12 cases (38.7%). Serum β2MG was elevated in 18 cases (58.1%). Angiotensin-converting enzyme (ACE) levels were normal, and rheumatoid factor and human T-cell lymphotropic virus type 1 (HTLV-1) antibody tests were negative in all patients. Krebs von den Lungen-6 (KL-6) was elevated in 22.6% of patients, and soluble interleukin-2 receptor (sIL-2R) was elevated in 66.7%. Treatments The treatments administered to the patients are shown in the Supplementary Table. All patients were treated with betamethasone eye drops. Two cases required subconjunctival dexamethasone injections, and one case required a sub-Tenon injection of triamcinolone acetonide (STTA). Seventeen cases (54.8%) received systemic corticosteroids (i.e., oral prednisolone or steroid pulse therapy). Of these, eight (25.8%) were prescribed systemic corticosteroids by internists or pediatricians for AIN, and nine (29.0%) were prescribed by ophthalmologists for uveitis. The ophthalmologists’ prescriptions were given for recurrent anterior uveitis in five cases (accompanied by optic disc swelling in three cases, vitreous opacity in one case, with macular edema in two cases). Prescriptions were also given for choroidal neovascularization in one case, optic disc neovascularization in one case, serous retinal detachment in one case, and as a continuation of a previous physician’s treatment for severe uveitis findings (details unknown) in one case. The initial prednisolone dose ranged from 10 to 60 mg/day (mean: 26.0 mg/day, excluding Case 11 and Case 31, who underwent steroid pulse therapy in internal medicine). In Case 8, the initial dose for choroidal neovascularization (CNV) was 60 mg/day. The average duration of prednisolone administration was 33.0 months. In addition to oral prednisolone, Case 19 was treated with methotrexate (MTX) for recurrent anterior uveitis, and Case 12 was treated with mizoribine for AIN. None of the patients received adalimumab (ADA). Recurrences of uveitis occurred in 20 cases (64.5%): 11 cases had one recurrence, six had two recurrences, and three had three recurrences. Of these, five cases required new prednisolone treatment at doses ranging from 20 to 60 mg. Nine cases were already receiving prednisolone at the time of recurrence, and three cases required an increased prednisolone dose. Ocular complications Ocular complications are shown in Table 5. During follow-up, seven eyes of five cases developed ocular hypertension, and four eyes of three cases required suture trabeculotomy. Disc neovascularization and vitreous hemorrhage were observed in two eyes (3.3%), and choroidal neovascularization (Fig. 2-F) and macular hole occurred in one eye (1.6%, overlapping). Visual and renal outcomes Remission of uveitis was achieved in 29 cases (93.5%). The mean age at remission was 16.0 years (range: 11–24 years). The follow-up period after remission was 1–182 months (mean: 74.3 months). At the last visit, 53 of 57 eyes (93.0%) had best-corrected visual acuity of 0.8 or better (Supplementary Table). Visual acuity decreased to 0.2 or less in two eyes due to macular complications, including CNV in one eye (1.8%), and a combination of cataract, glaucoma, and macular hole in one eye (1.8%, overlapping). Among the eight cases treated with systemic corticosteroids for AIN, four (50.0%) achieved complete recovery (creatinine 0.79 mg/dL) and required periodic follow-up (every 3 months to 1 year). Discussion TINU syndrome is fundamentally a diagnosis of exclusion, which introduces some ambiguity. According to the diagnostic criteria proposed by Mandeville et al., patients are classified as “definite,” “probable,” or “possible” based on the diagnostic certainty of TIN and the typicality of uveitis, after excluding other etiologies such as sarcoidosis, Behçet's disease, tuberculosis, and syphilis [ 3 ]. The “possible” category allows broader consideration of TINU syndrome. However, in this study, to clarify the clinical features more precisely, we excluded “possible” cases (i.e., incomplete TIN or atypical uveitis) and included only “definite” and “probable” cases. In 2021, the SUN Working Group published classification criteria for TINU syndrome. These differ from the diagnostic criteria but were developed using machine learning to minimize misclassification [ 8 ]. The current study included cases diagnosed by Mandeville’s criteria prior to the SUN classification. While largely similar—both exclude other diseases, require anterior uveitis, and require biopsy or clinical diagnosis of TIN—the definition of clinical TIN differs slightly. Based on the SUN criteria, five of our cases would have been excluded. Uveitis in TINU syndrome is typically characterized by anterior segment inflammation, with posterior uveitis or panuveitis reported in up to 20% of patients [ 3 , 9 – 11 ]. However, recent studies indicate a higher incidence of posterior ocular involvement. Uludag Kirimli et al. reported posterior ocular lesions in 69.2% of patients [ 12 ]. Our previous study (1993–2003) reported posterior segment findings in 11–56% of eyes, depending on the parameter assessed [ 4 ]. In the present study, posterior findings were observed in 78.7% of eyes. Even when mild findings (e.g., optic disc redness, swelling, or mild vitreous haze) were excluded, posterior segment involvement remained high at 62.3%. These results demonstrate that, contrary to conventional assumptions, posterior inflammation is common in TINU syndrome, and most cases are panuveitis, as demonstrated in the present study and a recent report [ 12 ]. Some patients developed a severe anterior chamber inflammation (≥ 3 cells) or posterior inflammation with choroidal or optic disc neovascularization or retinal exudates. Such cases require aggressive anti-inflammatory treatment to preserve visual function. Macular complications in particular c an lead to poor outcomes. In fact, two eyes in this study had poor visual acuity (0.2 and 0.1). The high incidence of posterior segment inflammation and poor-prognosis cases may reflect racial background, but there are no comparable large-scale studies from other Asian hospitals. Although TINU syndrome typically presents with a non-granulomatous uveitis [ 1 , 13 ], our study found granulomatous features such as mutton-fat keratic precipitates (17 eyes, 27.9%), iris nodules (9 eyes, 14.8%), and trabecular meshwork nodules (17 eyes, 27.9%). There is also a documented case of acute granulomatous iridocyclitis with a diagnosis of TINU syndrome, as confirmed by renal biopsy findings [ 14 ]. Thus, granulomatous findings should be recognized as possible in TINU syndrome. Elevated urine β2MG is a reliable marker for renal tubulointerstitial nephritis and correlates with histological severity [ 15 ]. Mandeville et al. included elevated urine β2MG in their diagnostic criteria because it was a highly sensitive marker for AIN [ 3 ]. Our previous study (1993–2003) found that 91.7% of patients had elevated urine β2MG, while only 25% had elevated serum Cre [ 4 ]. In the present study, all patients had elevated urine β2MG levels, with most exceeding five times the upper normal limit, whereas 38.7% had elevated serum Cre. Markedly elevated urine β2MG is therefore a hallmark of TINU syndrome. sIL-2R, released by activated T cells, is a sensitive marker of T cell activation and is elevated in sarcoidosis, malignant lymphoma, and atopic dermatitis [ 16 – 18 ]. In autoimmune TIN, serum sIL-2R levels are significantly higher than in patients with chronic kidney disease of other causes. A higher sIL-2R level was independently associated with renal recovery in multivariate analysis. Serum sIL-2R levels dropped after corticosteroid therapy, and the estimated glomerular filtration rate (eGFR) improved, especially in the high sIL-2R group [ 19 ]. This suggests a definitive association between sIL-2R and chronic renal disease activity. The high positive rate of 66.7% for sIL-2R in our study confirms that sIL-2R is a reliable marker for TINU syndrome. TINU syndrome is typically treated with corticosteroid eye drops alone, with oral prednisolone added for posterior segment inflammation. Recurrence often necessitates prolonged oral prednisolone, and additional immunosuppressants or TNF inhibitors may be required [ 3 , 20 – 23 ]. This study confirmed frequent recurrences, even during oral prednisolone treatment. Most patients achieved remission by the age of 24 (mean age 16.0 years), and no recurrence of uveitis was observed thereafter. The disease appears most active in childhood and then loses its activity. Adequate treatment during the active phases is essential to prevent the formation of scar lesions that can directly lead to visual dysfunction. In cases with insufficient response to prednisone alone, the combination use of immunosuppressants or TNF inhibitors is necessary. This study has limitations, including its retrospective, single-center design and racially homogenous Japanese cohort. International multicenter studies are needed for broader validation. In summary, posterior ocular inflammation is common in TINU syndrome. Both urine β2MG and sIL-2R are reliable diagnostic markers. Childhood-onset cases generally achieve remission by the age of 24. Declarations Conflict of Interest Statement The authors have no conflicts of interest to declare. Funding Sources This research was not sponsored by any organization, and there is no contribution from any of our colleagues other than the authors mentioned. The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Authors' contributions TI and KN initially designed the concept of this work. TI, KN, DI, KM, SK, KH, and KS collected the data. TI, KN analyzed the data and wrote the main manuscript text and KS prepared tables 1-5. SK, NK, and SI performed a critical review of the manuscript. All authors reviewed the manuscript. 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J AAPOS 25: 267 DOI 10.1016/j.jaapos.2021.03.017 Gion N, Stavrou P, Foster CS (2000) Immunomodulatory therapy for chronic tubulointerstitial nephritis–associated uveitis. Am J Ophthalmol 129: 764–8 DOI 10.1016/s0002-9394(00)00482-7 Tables Table 1. Number of cases classified in each of acute interstitial nephritis and uveitis (31 cases) Classification Acute interstitial nephritis Uveitis Total cases Histological Clinical Clinical Typical Atypical Complete Incomplete Definite 7 0 0 7 0 7 Probable 0 0 23 23 0 23 1 1 1 31 Table 2. Ocular symptoms at initial visit and laterality cases (%) Symptoms Redness Blurred vision Pain Decreased vision Floaters Tearing Upper eyelid swelling Photophobia 22 10 9 1 1 1 1 0 (71.0) (32.3) (29.0) (3.2) (3.2) (3.2) (3.2) (0) Laterality Bilateral Unilateral 30 1 (96.8) (3.2) Table 3. Ocular findings Ocular findings eyes (%) Anterior segment findings 61 （100） Conjunctival injection Iridocyclitis Anterior chamber cells ≧ 0.5+ ≧ 3+ Fibrin Fine keratic precipitates Mutton-fat keratic precipitates Iris nodule Trabecular meshwork nodule Peripheral anterior synechia Posterior synechiae Iris rubeosis 30 61 61 25 4 20 17 9 17 14 22 2 (49.2) (100) (100) (41.0) (6.6) (32.8) (27.9) (14.8) (27.9) (23.0) (36.1) (3.3) Posterior segment findings 48 (78.7) Anterior vitreous cells Optic disc redness Optic disc swelling Vitreous haze Snowball vitreous opacity Dilated retinal vessels Retinal exudates Serous retinal detachment 19 36 8 34 13 6 9 1 (31.1) (59.0) (13.1) (55.7) (21.3) (9.8) (14.8) (1.6) Table 4. Positive rates of Laboratory findings cases (%) Serum ACE 0/31 (0) BUN 0/31 (0) Cre 12/31 (38.7) β2MG 18/31 (58.1) KL-6 7/31 (22.6) sIL-2R 14/21 (66.7) IgG CRP Rheumatoid factor Antinuclear antibody 10/31 12/31 0/31 14/31 (32.3) (38.7) (0) (45.2) Urine Proteinuria 18/31 (58.1) Glucosuria 11/31 (35.5) White blood cells β2 microglobulin NAG 1/31 31/31 12/29 (3.2) (100) (41.4) ACE: angiotensin converting enzyme, BUN: blood urea nitrogen, Cre: creatinine β2MG: β2 microglobulin, KL-6: Krebs von den Lungen-6 sIL-2R: soluble interleukin-2 receptor, NAG: N-acetyl-beta-glucosaminidase Table 5. Ocular complications Complications eyes (%) OH/glaucoma Cataract Cystoid macular edema Choroidal neovascularization Disc neovascularization Vitreous hemorrhage Macular hole 7 2 4 1 2 2 1 (11.5) (3.3) (6.6) (1.6) (3.3) (3.3) (1.6) OH: Ocular hypertension Additional Declarations No competing interests reported. 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University","correspondingAuthor":false,"prefix":"","firstName":"Keitaro","middleName":"","lastName":"Hase","suffix":""},{"id":573845526,"identity":"f3ea7e72-8550-4d07-abdd-255c47983a96","order_by":6,"name":"Kayo Suzuki","email":"","orcid":"","institution":"Hokkaido University","correspondingAuthor":false,"prefix":"","firstName":"Kayo","middleName":"","lastName":"Suzuki","suffix":""},{"id":573845529,"identity":"1f5ae4e3-f42b-4623-abc8-e5e0cf5f0922","order_by":7,"name":"Nobuyoshi Kitaichi","email":"","orcid":"","institution":"Hokkaido University","correspondingAuthor":false,"prefix":"","firstName":"Nobuyoshi","middleName":"","lastName":"Kitaichi","suffix":""},{"id":573845530,"identity":"040496f9-5de2-4023-a161-d9188e86300b","order_by":8,"name":"Shigeaki Ohno","email":"","orcid":"","institution":"Hokkaido University","correspondingAuthor":false,"prefix":"","firstName":"Shigeaki","middleName":"","lastName":"Ohno","suffix":""},{"id":573845531,"identity":"dd31f446-d378-49c6-b9ca-0ac81d7d9212","order_by":9,"name":"Susumu Ishida","email":"","orcid":"","institution":"Hokkaido University","correspondingAuthor":false,"prefix":"","firstName":"Susumu","middleName":"","lastName":"Ishida","suffix":""}],"badges":[],"createdAt":"2026-01-07 01:38:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8535691/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8535691/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101497943,"identity":"58698e2f-137c-4fa5-b3d2-3a2a4ec391cf","added_by":"auto","created_at":"2026-01-30 12:58:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":192232,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAge and gender of patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMales are shown by filled squares and females are shown by open squares.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8535691/v1/b4212cd2751f504c37b2b39e.png"},{"id":101497944,"identity":"89fd930f-e4b6-44af-bc3c-5424db46ce1c","added_by":"auto","created_at":"2026-01-30 12:58:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":5962465,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOcular Findings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA: Mutton fat keratic precipitates\u003c/p\u003e\n\u003cp\u003eB: Koeppe iris nodule\u003c/p\u003e\n\u003cp\u003eC: Peripheral anterior synechia and trabecular meshwork nodule\u003c/p\u003e\n\u003cp\u003eD: Retinal exudates and snowball vitreous opacities\u003c/p\u003e\n\u003cp\u003eE: Vitreous hemorrhage from disc neovascularization on fluorescein angiography\u003c/p\u003e\n\u003cp\u003eF: Choroidal neovascularization on optical coherence tomography\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8535691/v1/bbc9e21e37c43f36e0aca2b9.png"},{"id":104399412,"identity":"92ba5576-ba98-41bd-be09-b32dd23a320c","added_by":"auto","created_at":"2026-03-11 12:06:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":10870488,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8535691/v1/9912992b-73f0-496c-8383-2d179ad01d25.pdf"},{"id":101497945,"identity":"7f51fd94-15c4-4623-95bb-f87d726c74a9","added_by":"auto","created_at":"2026-01-30 12:58:58","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":45720,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable.docx","url":"https://assets-eu.researchsquare.com/files/rs-8535691/v1/b253d6d702137d5133969699.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical Features of Tubulointerstitial Nephritis and Uveitis (TINU) Syndrome in Hokkaido, Japan","fulltext":[{"header":"Introduction","content":"\u003cp\u003eTubulointerstitial nephritis and uveitis (TINU) syndrome is a disorder characterized by idiopathic acute tubulointerstitial nephritis (AIN) accompanied with uveitis. It was first described by Dobrin et al. in 1975 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The pathogenesis remains incompletely understood; however, it is thought to involve an immune reaction against shared antigens in the uvea and renal tubular cells [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. TINU syndrome is often observed in adolescent females around the age of 15 [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] and is generally considered to have a relatively good prognosis, although reported outcomes vary [\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe previously reported on patients with TINU syndrome who first visited our hospital between 1993 and 2003 [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This report summarizes the clinical features of patients who newly presented thereafter.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEthics statement\u003c/h2\u003e \u003cp\u003eThis study was approved by the Hokkaido University Institutional Review Board for Clinical Research (No. 019\u0026ndash;0269). The tenets of the Declaration of Helsinki were followed, and the need for written informed consent was formally waived by the ethics committee.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSubjects\u003c/h3\u003e\n\u003cp\u003eNewly diagnosed TINU syndrome cases at Hokkaido University Hospital between January 2004 and December 2018 who were followed for more than six months were included in this study.\u003c/p\u003e \u003cp\u003eDiagnosis was confirmed by uveitis specialists based on criteria of Mandeville et al [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. These require the presence of both AIN and uveitis, along with the exclusion of other known systemic diseases that could cause either condition. Cases are categorized as \u0026ldquo;definite,\u0026rdquo; \u0026ldquo;probable,\u0026rdquo; or \u0026ldquo;possible\u0026rdquo; depending on whether uveitis is typical or atypical and whether AIN diagnosis is histological or clinical. This study included \u0026ldquo;definite\u0026rdquo; and \u0026ldquo;probable\u0026rdquo; cases, while two \u0026ldquo;possible\u0026rdquo; cases were excluded.\u003c/p\u003e \u003cp\u003eWe retrospectively collected demographic information, age, disease duration, anatomical localization, laterality, mode of onset, uveitis complications, and treatments from patients\u0026rsquo; medical records. Ocular findings were graded using the Standard Uveitis Nomenclature (SUN) criteria [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Recurrence was defined as \u0026ge;\u0026thinsp;2 anterior chamber cells or newly observed posterior segment findings. Remission was defined as inactive uveitis for at least six months after discontinuation of treatment. Ocular hypertension was defined as an intraocular pressure exceeding 21 mmHg on two or more occasions.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatients’ characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSixty-one eyes of 31 patients were included in this study. At first presentation, ages ranged from eight to 54 years (mean: 16.0 years), with 29 patients (93.5%) under 20 years old. Of these, 21 patients (67.7%) were female (Figure 1). Seven cases were classified as “definite” and 24 as “probable” TINU syndrome (Table 1). Uveitis was bilateral in 30 cases and unilateral in one. The follow-up period ranged from 12 to 188 months (mean: 94.8). None of the patients had suspected triggers such as infection, vaccination, or medication. Three patients were diagnosed with AIN before uveitis onset, while 28 were diagnosed concurrently with uveitis. No cases were diagnosed with AIN afterward.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOcular manifestations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOcular symptoms at onset are summarized in Table 2. The most common symptom was ocular redness (hyperemia) (71.0%), followed by blurred vision (32.3%) and ocular pain (29.0%). Ocular findings are shown in Table 3. Anterior segment involvement was present in all 61 eyes, while posterior segment findings were observed in 48 eyes (78.7%) (i.e., only anterior segment findings were seen in 21.3% of eyes). Severe iridocyclitis (≥ 3 anterior chamber cells) was present in 25 eyes (41.0%), and inflammatory iris rubeosis occurred in two eyes. Keratic precipitates were found in 37 eyes (60.7%), with mutton-fat keratic precipitates in 17 eyes (27.9%) (Fig. 2-A). Posterior synechia was seen in 22 eyes (36.1%). Iris nodules (Fig. 2-B) were found in nine eyes (14.8%) and trabecular meshwork nodules (Fig. 2-C) in 17 eyes (27.9%).\u003c/p\u003e\n\u003cp\u003ePosterior segment findings included optic disc redness (36 eyes, 59.0%) and vitreous haze (34 eyes, 55.7%), with either present in 47 eyes (77.0%). Other findings included snowball vitreous opacities in 13 eyes (21.3%), dilated retinal vessels in six eyes (9.8%), and retinal exudates in nine eyes (14.8%). Fluorescein fundus angiography was performed in 14 eyes (7 patients). Optic disc hyperfluorescence was seen in six eyes (42.9%), leakage from retinal vessels in seven eyes (50.0%), and leakage from optic disc neovascularization (Fig. 2-E) in one eye (7.1%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLaboratory findings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUrinalysis and blood tests were performed in all patients at the first visit to our hospital (Table 4). Urine β2 microglobulin (β2MG) was elevated in all patients with a mean value of 4.80 (normal range: 0.027–0.275 mg/L). In 20 cases, levels were more than five times the upper limit, and in 11 cases, they were more than 10 times the upper limit. Urine N-acetylglucosaminidase (NAG) levels were elevated in 12 of 29 cases (41.4%). Proteinuria and glucosuria were present in 18 cases (58.1%) and 11 cases (35.5%), respectively.\u003c/p\u003e\n\u003cp\u003eBlood tests showed normal blood urea nitrogen in all patients. Serum creatinine (Cre) was slightly elevated (up to 1.6 mg/dL; normal range: 0.4–0.7 mg/dL in females and 0.4–1.1 mg/dL in males) in 12 cases (38.7%). Serum β2MG was elevated in 18 cases (58.1%). Angiotensin-converting enzyme (ACE) levels were normal, and rheumatoid factor and human T-cell lymphotropic virus type 1 (HTLV-1) antibody tests were negative in all patients. Krebs von den Lungen-6 (KL-6) was elevated in 22.6% of patients, and soluble interleukin-2 receptor (sIL-2R) was elevated in 66.7%.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe treatments administered to the patients are shown in the Supplementary Table. All patients were treated with betamethasone eye drops. Two cases required subconjunctival dexamethasone injections, and one case required a sub-Tenon injection of triamcinolone acetonide (STTA). Seventeen cases (54.8%) received systemic corticosteroids (i.e., oral prednisolone or steroid pulse therapy). Of these, eight (25.8%) were prescribed systemic corticosteroids by internists or pediatricians for AIN, and nine (29.0%) were prescribed by ophthalmologists for uveitis.\u003c/p\u003e\n\u003cp\u003eThe ophthalmologists’ prescriptions were given for recurrent anterior uveitis in five cases (accompanied by optic disc swelling in three cases, vitreous opacity in one case, with macular edema in two cases). Prescriptions were also given for choroidal neovascularization in one case, optic disc neovascularization in one case, serous retinal detachment in one case, and as a continuation of a previous physician’s treatment for severe uveitis findings (details unknown) in one case. The initial prednisolone dose ranged from 10 to 60 mg/day (mean: 26.0 mg/day, excluding Case 11 and Case 31, who underwent steroid pulse therapy in internal medicine). In Case 8, the initial dose for choroidal neovascularization (CNV) was 60 mg/day. The average duration of prednisolone administration was 33.0 months. In addition to oral prednisolone, Case 19 was treated with methotrexate (MTX) for recurrent anterior uveitis, and Case 12 was treated with mizoribine for AIN. None of the patients received adalimumab (ADA).\u003c/p\u003e\n\u003cp\u003eRecurrences of uveitis occurred in 20 cases (64.5%): 11 cases had one recurrence, six had two recurrences, and three had three recurrences. Of these, five cases required new prednisolone treatment at doses ranging from 20 to 60 mg. Nine cases were already receiving prednisolone at the time of recurrence, and three cases required an increased prednisolone dose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOcular complications\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOcular complications are shown in Table 5. During follow-up, seven eyes of five cases developed ocular hypertension, and four eyes of three cases required suture trabeculotomy. Disc neovascularization and vitreous hemorrhage were observed in two eyes (3.3%), and choroidal neovascularization (Fig. 2-F) and macular hole occurred in one eye (1.6%, overlapping).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVisual and renal outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRemission of uveitis was achieved in 29 cases (93.5%). The mean age at remission was 16.0 years (range: 11–24 years). The follow-up period after remission was 1–182 months (mean: 74.3 months). At the last visit, 53 of 57 eyes (93.0%) had best-corrected visual acuity of 0.8 or better (Supplementary Table). Visual acuity decreased to 0.2 or less in two eyes due to macular complications, including CNV in one eye (1.8%), and a combination of cataract, glaucoma, and macular hole in one eye (1.8%, overlapping).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAmong the eight cases treated with systemic corticosteroids for AIN, four (50.0%) achieved complete recovery (creatinine \u0026lt; 0.79 mg/dL). The remaining four cases (50.0%) continued to show slight creatinine elevation (\u0026gt; 0.79 mg/dL) and required periodic follow-up (every 3 months to 1 year).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTINU syndrome is fundamentally a diagnosis of exclusion, which introduces some ambiguity. According to the diagnostic criteria proposed by Mandeville et al., patients are classified as \u0026ldquo;definite,\u0026rdquo; \u0026ldquo;probable,\u0026rdquo; or \u0026ldquo;possible\u0026rdquo; based on the diagnostic certainty of TIN and the typicality of uveitis, after excluding other etiologies such as sarcoidosis, Beh\u0026ccedil;et's disease, tuberculosis, and syphilis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The \u0026ldquo;possible\u0026rdquo; category allows broader consideration of TINU syndrome. However, in this study, to clarify the clinical features more precisely, we excluded \u0026ldquo;possible\u0026rdquo; cases (i.e., incomplete TIN or atypical uveitis) and included only\u003c/p\u003e \u003cp\u003e\u0026ldquo;definite\u0026rdquo; and \u0026ldquo;probable\u0026rdquo; cases.\u003c/p\u003e \u003cp\u003eIn 2021, the SUN Working Group published classification criteria for TINU syndrome. These differ from the diagnostic criteria but were developed using machine learning to minimize misclassification [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The current study included cases diagnosed by Mandeville\u0026rsquo;s criteria prior to the SUN classification. While largely similar\u0026mdash;both exclude other diseases, require anterior uveitis, and require biopsy or clinical diagnosis of TIN\u0026mdash;the definition of clinical TIN differs slightly. Based on the SUN criteria, five of our cases would have been excluded.\u003c/p\u003e \u003cp\u003eUveitis in TINU syndrome is typically characterized by anterior segment inflammation, with posterior uveitis or panuveitis reported in up to 20% of patients [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, recent studies indicate a higher incidence of posterior ocular involvement. Uludag Kirimli et al. reported posterior ocular lesions in 69.2% of patients [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Our previous study (1993\u0026ndash;2003) reported posterior segment findings in 11\u0026ndash;56% of eyes, depending on the parameter assessed [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In the present study, posterior findings were observed in 78.7% of eyes. Even when mild findings (e.g., optic disc redness, swelling, or mild vitreous haze) were excluded, posterior segment involvement remained high at 62.3%. These results demonstrate that, contrary to conventional assumptions, posterior inflammation is common in TINU syndrome, and most cases are panuveitis, as demonstrated in the present study and a recent report [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSome patients developed a severe anterior chamber inflammation (\u0026ge;\u0026thinsp;3 cells) or posterior inflammation with choroidal or optic disc neovascularization or retinal exudates. Such cases require aggressive anti-inflammatory treatment to preserve visual function. Macular complications in particular \u003cb\u003ec\u003c/b\u003ean lead to poor outcomes. In fact, two eyes in this study had poor visual acuity (0.2 and 0.1). The high incidence of posterior segment inflammation and poor-prognosis cases may reflect racial background, but there are no comparable large-scale studies from other Asian hospitals.\u003c/p\u003e \u003cp\u003eAlthough TINU syndrome typically presents with a non-granulomatous uveitis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], our study found granulomatous features such as mutton-fat keratic precipitates (17 eyes, 27.9%), iris nodules (9 eyes, 14.8%), and trabecular meshwork nodules (17 eyes, 27.9%). There is also a documented case of acute granulomatous iridocyclitis with a diagnosis of TINU syndrome, as confirmed by renal biopsy findings [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Thus, granulomatous findings should be recognized as possible in TINU syndrome.\u003c/p\u003e \u003cp\u003eElevated urine β2MG is a reliable marker for renal tubulointerstitial nephritis and correlates with histological severity [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Mandeville et al. included elevated urine β2MG in their diagnostic criteria because it was a highly sensitive marker for AIN [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Our previous study (1993\u0026ndash;2003) found that 91.7% of patients had elevated urine β2MG, while only 25% had elevated serum Cre [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In the present study, all patients had elevated urine β2MG levels, with most exceeding five times the upper normal limit, whereas 38.7% had elevated serum Cre. Markedly elevated urine β2MG is therefore a hallmark of TINU syndrome.\u003c/p\u003e \u003cp\u003esIL-2R, released by activated T cells, is a sensitive marker of T cell activation and is elevated in sarcoidosis, malignant lymphoma, and atopic dermatitis [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In autoimmune TIN, serum sIL-2R levels are significantly higher than in patients with chronic kidney disease of other causes. A higher sIL-2R level was independently associated with renal recovery in multivariate analysis. Serum sIL-2R levels dropped after corticosteroid therapy, and the estimated glomerular filtration rate (eGFR) improved, especially in the high sIL-2R group [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. This suggests a definitive association between sIL-2R and chronic renal disease activity. The high positive rate of 66.7% for sIL-2R in our study confirms that sIL-2R is a reliable marker for TINU syndrome.\u003c/p\u003e \u003cp\u003eTINU syndrome is typically treated with corticosteroid eye drops alone, with oral prednisolone added for posterior segment inflammation. Recurrence often necessitates prolonged oral prednisolone, and additional immunosuppressants or TNF inhibitors may be required [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR21 CR22\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. This study confirmed frequent recurrences, even during oral prednisolone treatment.\u003c/p\u003e \u003cp\u003eMost patients achieved remission by the age of 24 (mean age 16.0 years), and no recurrence of uveitis was observed thereafter. The disease appears most active in childhood and then loses its activity. Adequate treatment during the active phases is essential to prevent the formation of scar lesions that can directly lead to visual dysfunction. In cases with insufficient response to prednisone alone, the combination use of immunosuppressants or TNF inhibitors is necessary.\u003c/p\u003e \u003cp\u003eThis study has limitations, including its retrospective, single-center design and racially homogenous Japanese cohort. International multicenter studies are needed for broader validation.\u003c/p\u003e \u003cp\u003eIn summary, posterior ocular inflammation is common in TINU syndrome. Both urine β2MG and sIL-2R are reliable diagnostic markers. Childhood-onset cases generally achieve remission by the age of 24.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was not sponsored by any organization, and there is no contribution from any of our colleagues other than the authors mentioned. The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTI and KN initially designed the concept of this work. TI, KN, DI, KM, SK, KH, and KS collected the data. TI, KN analyzed the data and wrote the main manuscript text and KS prepared tables 1-5. SK, NK, and SI performed a critical review of the manuscript. All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData are available upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eDobrin RS, Vernier RL, Fish AL (1975) Acute eosinophilic interstitial nephritis and renal failure with bone marrow-lymph node granulomas and anterior uveitis. A new syndrome. Am J Med 59: 325\u0026ndash;33 DOI 10.1016/0002-9343(75)90390-3\u003c/li\u003e\n \u003cli\u003eWakaki H, Sakamoto H, Awazy M (2001) Tubulointerstitial nephritis and uveitis syndrome with autoantibody directed to renal tubular cells. Pediatrics 107: 1443\u0026ndash;6 DOI 10.1542/peds.107.6.1443\u003c/li\u003e\n \u003cli\u003eMandeville J, Levinson R, Holland G (2001) The tubulointerstitial nephritis and uveitis syndrome. Surv Ophthalmol 46: 195\u0026ndash;208 DOI 10.1016/s0039-6257(01)00261-2\u003c/li\u003e\n \u003cli\u003eGoda C, Kotake S, Ichiishi A, Namba K, Kitaichi N, Ohno S (2005) Clinical features in tubulointerstitial nephritis and uveitis (TINU) syndrome. Am J Ophthalmol 140: 637\u0026ndash;41 DOI 10.1016/j.ajo.2005.04.019\u003c/li\u003e\n \u003cli\u003eSobolewska B, Bayyoud T, Deuter C, Doycheva D, Zierhut M (2018) Long-Term follow-up of patients with tubulointerstitial nephritis and uveitis (TINU) syndrome. Ocul Immunol Inflamm 26: 601\u0026ndash;7 DOI 10.1080/09273948.2016.1247872\u003c/li\u003e\n \u003cli\u003eOkafor LO, Hewins P, Murray PI, Denniston AK (2017) Tubulointerstitial nephritis and uveitis (TINU) syndrome: a systematic review of its epidemiology, demographics and risk factors. Orphanet J Rare Dis 12: 128 DOI 1186/s13023-017-0677-2\u003c/li\u003e\n \u003cli\u003eStandardization of Uveitis Nomenclature Working G (2021) Classification criteria for tubulointerstitial nephritis with uveitis syndrome. Am J Ophthalmol 228:255-61 DOI 10.1016/j.ajo.2021.03.041\u003c/li\u003e\n \u003cli\u003eSinnamon KT, Courtney AE, Harron C, O\u0026rsquo;Rourke Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of Uveitis Nomenclature (SUN) Working Group (2005) Standardization of uveitis nomenclature for reporting clinical data. Results of the first international workshop. Am J Ophthalmol 140: 509\u0026ndash;16 DOI 10.1016/j.ajo.2005.03.057\u003c/li\u003e\n \u003cli\u003eSaarela V, Nuutinen M, Ala-Houhala M, Arikoski P, R\u0026ouml;nnholm K, Jahnukainen T (2013) Tubulointerstitial nephritis and uveitis syndrome in children: a prospective multicenter study. Ophthalmology 120: 1476\u0026ndash;81 DOI 10.1016/j.ophtha.2012.12.039\u003c/li\u003e\n \u003cli\u003eShi J, Xu S, Chen J, Wu H (2024) Clinical manifestations and outcomes in tubulointerstitial nephritis and uveitis syndrome: a case report and a systematic review in China. Int Urol Nephrol 56: \u0026nbsp;1415-27 DOI 10.1007/s11255-023-03797-6\u003c/li\u003e\n \u003cli\u003eParoli MP, Cappiello D, Staccini D, Caccavale R, Paroli M (2022) Tubulointerstitial Nephritis and Uveitis Syndrome (TINU): A Case Series in a Tertiary Care Uveitis Setting. J Clin Med 25: 4995 DOI 10.3390/jcm11174995\u003c/li\u003e\n \u003cli\u003eUludag Kirimli G, Hassan M, Onghanseng N, Or C, Yasar C, Park S, Akhavanrezayat A, Mobasserian A, Yavari N, Bazojoo V, Khojasteh H, Ghoraba H, Karaca I, Trong Tuong Than N, Zaidi M, Nguyen QD (2024) Ocular manifestations and clinical outcomes in Tubulointerstitial Nephritis and Uveitis Syndrome (TINU). Eye (Lond) 38: 349-56 DOI 10.1038/s41433-023-02695-6\u003c/li\u003e\n \u003cli\u003eMackensen F, Billing H (2009) Tubulointerstitial nephritis and uveitis syndrome.\u0026nbsp;Curr Opin Ophthalmol20: 525\u0026ndash;531 DOI 10.1097/ICU.0b013e3283318f9a\u003c/li\u003e\n \u003cli\u003eBarut K, Rzayev T, Canpolat N, Ozluk Y, Tugal-Tutkun I,\u0026nbsp;Kasapcopur O(2015) Acute granulomatous iridocyclitis in a child of tubulointerstitial nephritis and uveitis syndrome. J Ophthalmic Inflamm Infect 5 DOI 10.1186/s12348-015-0035-2\u003c/li\u003e\n \u003cli\u003eTakemura T, Okada M, Hino S, Fukushima K, Yamamoto S, Miyazato H, Maruyama K, Yoshioka K (1999) Course and outcome of tubulointerstitial nephritis and uveitis syndrome. Am J Kidney Dis 34: 1016\u0026ndash;21 DOI 10.1016/S0272-6386(99)70006-5\u003c/li\u003e\n \u003cli\u003eEurelings LEM, Miedema JR, Dalm VASH, van Daele PLA, van Hagen PM, van Laar JAM, Dik WA (2019) Sensitivity and specificity of serum soluble interleukin-2 receptor for diagnosing sarcoidosis in a population of patients suspected of sarcoidosis. PLoS One 14 DOI 0.1371/journal.pone.0223897\u003c/li\u003e\n \u003cli\u003eMurakami J, Arita K, Wada A, Mihara H, Origasa H, Kigawa M, Yasuda I, Sato T (2019) Serum soluble interleukin-2 receptor levels for screening for malignant lymphomas and differential diagnosis from other conditions. Mol Clin Oncol 11: 474-82 DOI 10.3892/mco.2019.1922\u003c/li\u003e\n \u003cli\u003eW\u0026uuml;thrich B, Joller-Jemelka H, Helfenstein U, Grob PJ (1990) Levels of soluble interleukin-2 receptors correlate with the severity of atopic dermatitis. Dermatologica 181: 92-7 DOI 10.1159/000247893\u003c/li\u003e\n \u003cli\u003eShiratori-Aso S, Nakazawa D, Nishino S, Ueda Y, Eguchi M, Yokoyama A, Yoshikawa J, Kudo T, Watanabe-Kusunoki K, Takaeda-Otera S, Yamamoto J, Matsuoka N, Kaneshima N, Hattanda F, Iwasaki S, Tsuji T, Fukasawa Y, Atsumi T (2022) Soluble Interleukin-2 Receptor predicts treatment outcome in patients with autoimmune tubulointerstitial nephritis. A preliminary study. Frontiers in Medicine 9 DOI 10.3389/fmed.2022.827388\u003c/li\u003e\n \u003cli\u003eProvencher LM, Fairbanks AM, Abramoff MD, Syed NA\u0026nbsp;(2018) Urinary \u0026beta;2-microglobulin and disease activity in patients with tubulointerstitial nephritis and uveitis syndrome. J Ophthalmic Inflamm Infect 8: 24 DOI 10.1186/s12348-018-0166-3\u003c/li\u003e\n \u003cli\u003ePakzad-Vaezi K, Pepple KL (2017) Tubulointerstitial nephritis and uveitis. Curr Opin Ophthalmol 28: 629\u0026ndash;35 DOI 10.1097/ICU.0000000000000421\u003c/li\u003e\n \u003cli\u003eTirelli F, Shafer BM, Davidson SL, Lerman MA (2021) Immunomodulation and TNF-\u0026alpha; inhibition for tubulointerstitial nephritis and uveitis syndrome: a case series. J AAPOS 25: 267 DOI 10.1016/j.jaapos.2021.03.017\u003c/li\u003e\n \u003cli\u003eGion N, Stavrou P, Foster CS (2000) Immunomodulatory therapy for chronic tubulointerstitial nephritis\u0026ndash;associated uveitis. Am J Ophthalmol 129: 764\u0026ndash;8 DOI 10.1016/s0002-9394(00)00482-7\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eNumber of cases classified in each of acute interstitial nephritis and uveitis (31 cases)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 118px;\"\u003e\n \u003cp\u003eClassification\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 291px;\"\u003e\n \u003cp\u003eAcute interstitial nephritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 180px;\"\u003e\n \u003cp\u003eUveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 94px;\"\u003e\n \u003cp\u003eTotal cases\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 94px;\"\u003e\n \u003cp\u003eHistological\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003eClinical\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eClinical\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 95px;\"\u003e\n \u003cp\u003eTypical\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 85px;\"\u003e\n \u003cp\u003eAtypical\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003eComplete\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eIncomplete\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003eDefinite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 118px;\"\u003e\n \u003cp\u003eProbable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eTable 2.\u0026nbsp;\u003c/strong\u003eOcular symptoms at initial visit and laterality\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003ecases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eSymptoms\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eRedness\u003c/p\u003e\n \u003cp\u003eBlurred vision\u003c/p\u003e\n \u003cp\u003ePain\u003c/p\u003e\n \u003cp\u003eDecreased vision\u003c/p\u003e\n \u003cp\u003eFloaters\u003c/p\u003e\n \u003cp\u003eTearing\u003c/p\u003e\n \u003cp\u003eUpper eyelid swelling\u003c/p\u003e\n \u003cp\u003ePhotophobia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e(71.0)\u003c/p\u003e\n \u003cp\u003e(32.3)\u003c/p\u003e\n \u003cp\u003e(29.0)\u003c/p\u003e\n \u003cp\u003e(3.2)\u003c/p\u003e\n \u003cp\u003e(3.2)\u003c/p\u003e\n \u003cp\u003e(3.2)\u003c/p\u003e\n \u003cp\u003e(3.2)\u003c/p\u003e\n \u003cp\u003e(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eLaterality\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eBilateral\u003c/p\u003e\n \u003cp\u003eUnilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e(96.8)\u003c/p\u003e\n \u003cp\u003e(3.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eTable 3.\u0026nbsp;\u003c/strong\u003eOcular findings\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eOcular findings\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eeyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eAnterior segment findings\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e（100）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eConjunctival injection\u003c/p\u003e\n \u003cp\u003eIridocyclitis\u003c/p\u003e\n \u003cp\u003eAnterior chamber cells\u003c/p\u003e\n \u003cp\u003e≧ 0.5+\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e≧ 3+\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eFibrin\u003c/p\u003e\n \u003cp\u003eFine keratic precipitates\u003c/p\u003e\n \u003cp\u003eMutton-fat keratic precipitates\u003c/p\u003e\n \u003cp\u003eIris nodule\u003c/p\u003e\n \u003cp\u003eTrabecular meshwork nodule\u003c/p\u003e\n \u003cp\u003ePeripheral anterior synechia\u003c/p\u003e\n \u003cp\u003ePosterior synechiae\u003c/p\u003e\n \u003cp\u003eIris rubeosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e(49.2)\u003c/p\u003e\n \u003cp\u003e(100)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(100)\u003c/p\u003e\n \u003cp\u003e(41.0)\u003c/p\u003e\n \u003cp\u003e(6.6)\u003c/p\u003e\n \u003cp\u003e(32.8)\u003c/p\u003e\n \u003cp\u003e(27.9)\u003c/p\u003e\n \u003cp\u003e(14.8)\u003c/p\u003e\n \u003cp\u003e(27.9)\u003c/p\u003e\n \u003cp\u003e(23.0)\u003c/p\u003e\n \u003cp\u003e(36.1)\u003c/p\u003e\n \u003cp\u003e(3.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003ePosterior segment findings\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e(78.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eAnterior vitreous cells\u003c/p\u003e\n \u003cp\u003eOptic disc redness\u003c/p\u003e\n \u003cp\u003eOptic disc swelling\u003c/p\u003e\n \u003cp\u003eVitreous haze\u003c/p\u003e\n \u003cp\u003eSnowball vitreous opacity\u003c/p\u003e\n \u003cp\u003eDilated retinal vessels\u003c/p\u003e\n \u003cp\u003eRetinal exudates\u003c/p\u003e\n \u003cp\u003eSerous retinal detachment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e(31.1)\u003c/p\u003e\n \u003cp\u003e(59.0)\u003c/p\u003e\n \u003cp\u003e(13.1)\u003c/p\u003e\n \u003cp\u003e(55.7)\u003c/p\u003e\n \u003cp\u003e(21.3)\u003c/p\u003e\n \u003cp\u003e(9.8)\u003c/p\u003e\n \u003cp\u003e(14.8)\u003c/p\u003e\n \u003cp\u003e(1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\n\u003cp\u003e\u003cstrong\u003eTable 4.\u0026nbsp;\u003c/strong\u003ePositive rates of Laboratory findings\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003ecases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eSerum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e ACE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0/31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e BUN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0/31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e Cre\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e12/31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e(38.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e \u0026beta;2MG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e18/31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e(58.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e KL-6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e7/31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e(22.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e sIL-2R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e14/21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e(66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e IgG\u003c/p\u003e\n \u003cp\u003e CRP\u003c/p\u003e\n \u003cp\u003e Rheumatoid factor\u003c/p\u003e\n \u003cp\u003e Antinuclear antibody\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e10/31\u003c/p\u003e\n \u003cp\u003e12/31\u003c/p\u003e\n \u003cp\u003e0/31\u003c/p\u003e\n \u003cp\u003e14/31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e(32.3)\u003c/p\u003e\n \u003cp\u003e(38.7)\u003c/p\u003e\n \u003cp\u003e(0)\u003c/p\u003e\n \u003cp\u003e(45.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eUrine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e Proteinuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e18/31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e(58.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e Glucosuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e11/31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e(35.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e White blood cells\u003c/p\u003e\n \u003cp\u003e \u0026beta;2 microglobulin\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e NAG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e1/31\u003c/p\u003e\n \u003cp\u003e31/31\u003c/p\u003e\n \u003cp\u003e12/29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e(3.2)\u003c/p\u003e\n \u003cp\u003e(100)\u003c/p\u003e\n \u003cp\u003e(41.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eACE: angiotensin converting enzyme, BUN: blood urea nitrogen, Cre: creatinine\u003c/p\u003e\n\u003cp\u003e\u0026beta;2MG:\u0026nbsp;\u0026beta;2 microglobulin, KL-6: Krebs von den Lungen-6\u003c/p\u003e\n\u003cp\u003esIL-2R: soluble interleukin-2 receptor, NAG: N-acetyl-beta-glucosaminidase\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5.\u0026nbsp;\u003c/strong\u003eOcular complications\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eComplications\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eeyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eOH/glaucoma\u003c/p\u003e\n \u003cp\u003eCataract\u003c/p\u003e\n \u003cp\u003eCystoid macular edema\u003c/p\u003e\n \u003cp\u003eChoroidal neovascularization\u003c/p\u003e\n \u003cp\u003eDisc neovascularization\u003c/p\u003e\n \u003cp\u003eVitreous hemorrhage\u003c/p\u003e\n \u003cp\u003eMacular hole\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e(11.5)\u003c/p\u003e\n \u003cp\u003e(3.3)\u003c/p\u003e\n \u003cp\u003e(6.6)\u003c/p\u003e\n \u003cp\u003e(1.6)\u003c/p\u003e\n \u003cp\u003e(3.3)\u003c/p\u003e\n \u003cp\u003e(3.3)\u003c/p\u003e\n \u003cp\u003e(1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eOH: Ocular hypertension\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"tubulointerstitial nephritis and uveitis (TINU) syndrome, β2-microglobulin, soluble interleukin-2 receptor (sIL-2R), corticosteroids","lastPublishedDoi":"10.21203/rs.3.rs-8535691/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8535691/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAlthough tubulointerstitial nephritis and uveitis (TINU) syndrome is considered to have a relatively good prognosis, its actual clinical features are not well understood. This study examined the clinical features of TINU syndrome cases that visited our hospital.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePatients who visited Hokkaido University Hospital and were diagnosed with TINU syndrome between 2004 and 2018 were included. Ocular findings, laboratory results, and treatment records were retrospectively reviewed from clinical charts.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eA total of 61 eyes from 31 patients were included: seven “definite” and 24 “probable” TINU cases. Age at first examination ranged from eight to 54 years (mean 16.0 years). Anterior uveitis was present in all eyes, while posterior segment inflammation was found in 79%, including vitreous haze, optic disc redness, dilated retinal vessels, retinal exudates, and serous retinal detachment. Urine β2-microglobulin was elevated in all patients, and serum soluble interleukin-2 receptor (sIL-2R) was elevated in 67%. Oral corticosteroids were required in 55% of patients, and recurrence occurred in 65%. Most cases achieved remission of uveitis by age 24. Final corrected visual acuity was 0.8 or better in 93% of patients, while 4% had 0.2 or worse.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eMore than three-quarters of cases showed not only anterior chamber inflammation but also posterior ocular inflammatory findings. Elevated sIL-2R was a reliable marker for TINU syndrome. Most cases achieved remission by adulthood and had a good visual prognosis, although some experienced poor outcomes due to ocular complications.\u003c/p\u003e","manuscriptTitle":"Clinical Features of Tubulointerstitial Nephritis and Uveitis (TINU) Syndrome in Hokkaido, Japan","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-30 12:58:53","doi":"10.21203/rs.3.rs-8535691/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"73c143e8-b89b-469f-ad14-9e70165cba9b","owner":[],"postedDate":"January 30th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-28T07:43:41+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-30 12:58:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8535691","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8535691","identity":"rs-8535691","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}