Table 1 List of published case series with two or more patients, published after the year 2010
From: Tubulointerstitial nephritis and uveitis syndrome in an adolescent female: a case report
No. of patients | Presentation | Laboratory findings | Renal biopsy | Treatment | Outcome | Important contribution | |
|---|---|---|---|---|---|---|---|
Weinstein et al. (2010), Israel [34] | 5 | Four women and one man aged 18-64 years with systemic symptoms, all with renal (and two with ocular) involvement at initial presentation | Moderate-to-severe renal dysfunction, proteinuria, elevated ESR, anemia | Renal biopsy in all patients, with moderate-to-severe interstitial nephritis | All Pt on systemic steroids, three on either cyclosporin or azathioprine | Uveitis relapse in 3/5 Pt after corticosteroid cessation, necessitating immune-modulatory agents | Adult patients with TINU had more severe uveitis than previously reported |
Biester et al. (2010), Germany [35] | 2 | 13-year-old boy and 5 years later 17-year-old girl with acute anterior uveitis | Pt 1: systemic inflammation, renal dysfunction Pt 2: elevated serum β-2 microglobulin, proteinuria | Pt 1: interstitial nephritis Pt 2: no signs of interstitial nephritis on repeated renal biopsies | Pt 1: topical and systemic steroid; mycophenolate-mofetil after frequent relapses Pt 2: topical prednisolone | Frequent relapses of acute uveitis in 1/2 Pt | Two familial TINU cases with specific HLA-DQB1 and -DRB1 alleles |
Tan et al. (2011), People’s Republic of China [4] | 9 | Seven female and two male Pt; mean age 45.2 years | Acute kidney injury (mean serum creatinine 241 µmol/L), mCRP serum autoantibodies in all Pt | Renal biopsy in all TINU cases; all samples positive for mCRP immunohistochemistry in tubules and interstitium | Topical ocular steroid in all patients, oral prednisone in 8/9 patients (median 30 mg/day), cyclophosphamide in 2/9 patients | Serum creatinine of all Pt normalized within 2–4 months after therapy initiation | High prevalence of serum anti-mCRP autoantibodies in patients with TINU syndrome |
Houghton et al. (2012), Oregon [36] | 4 | Three male and one female Pt aged 13–36 years | NA | Lymphocyte-dominant interstitial inflammation accompanied by lymphocytic tubulitis | NA | NA | TINU is usually not associated with IgG4 sclerosing disease |
Birnbaum et al. (2012), Illinois [37] | 2 | 5-year-old and 51-year-old patient. Rash in 1/2 Pt | Both Pt with elevated serum β-2 microglobulin | NA | NA | None had active chronic disease | Simultaneous-onset bilateral acute anterior uveitis is more common in younger patients and in TINU |
Peräsaari et al. (2013), Finland [18] | 20 | Ten male and ten female Pt, median age 12.8 years. Anterior uveitis in 20/20 Pt. Two Pt had uveitis prior to nephritis, 11 simultaneous with and 7 Pt ≥1 month after nephritis onset. | NA | Biopsy-proven AIN (not otherwise specified) | NA | All PT followed-up by a pediatric ophtalmologist and monthly by a pediatric nephrologist for at least 12 months | Strong associations exist between certain HLA genotypes in TIN(U) patients |
Saarela et al. (2013), Finland [2] | 16 | Eight male and eight female PT. Median age of uveitis onset 12 years and 9 months. Bilateral uveitis in all Pt. No ocular symptoms in 8/16 Pt | NA | Biopsy-proven AIN (not otherwise specified) | All 16 Pt received topical steroids. Mydriatics and antiglaucoma therapy used in 9/16 and 6/10 Pt, respectively. Prednisone or placebo per trial protocol | Follow-up duration between 6 and 48 months | No statistically significant difference in occurrence of uveitis in AIN patients, treated with prednisone or placebo |
Takemoto et al. (2013), Japan [38] | 2 | 12-year-old girl and a 12-year-old boy with probable TINU syndrome | Important elevation of urinary β-2 microglobulin in both patients | Not performed. | Pt 1: after several ocular inflammatory exacerbations with systemic steroid therapy, intravitreal bevacizumab proved useful Pt 2: topical and systemic corticosteroid | Pt 1: without choroidal neovascularization in 5 years’ time Pt 2: NA | Two cases of choroidal neovascularization in TINU, one successfully treated with intravitreal bevacizumab injection |
Li et al. (2014), People’s Republic of China [39] | 31 | Mean age 47 years, with a 5.2:1 female predominance. Median time from onset of symptoms to renal biopsy was 30 days | Increased serum creatinine, increased urinary α-1 microglobulin excretion and decreased urine osmolality in all Pt. Approximately 50% of Pt had elevated urinary NAG excretion and leukocyturia | Performed in all patients, together with mCRP-antibody and Krebs von den Lungen-6 assays | Systemic prednisone for 6–8 weeks and subsequently tapered. 10/31 Pt received methylprednisolone pulse therapy. Cyclophosphamide used in 11/31 Pt | Median follow-up period 37 months. Approximately one-third of patients had relapses during follow-up, and most had incomplete renal recovery | Uveitis in TINU can present well after onset of AIN, leading to misdiagnosis. Elevated mCRP-antibody levels may be useful to predict late-onset uveitis occurrence |
Reddy et al. (2014), Virginia [21] | 6 | Four boys and two girls with definite TINU, median age of 11 years. Diagnosis of renal disease before uveitis by a median of 3 months | NA | NA | All Pt received oral corticosteroids. 3/6 Pt treated with methotrexate and 4 Pt with mycophenolate mofetil, and one each received infliximab or cyclosporine | Median follow-up was 3.5 years. 2/6 Pt who completed therapy were successfully weaned from immunosuppressive therapy. | Panuveitis is underappreciated as a manifestation of TINU |
Ali et al. (2014), Oregon [40] | 4 | One Pt with definite and three with “possible or probable” TINU diagnosis, aged 10–31 years | Pt 1: mild anemia, elevated ESR and CRP, normal urinalysis Pt 2: elevated serum creatinine Pt 3: elevated serum creatinine and urine leukocyte esterase Pt 4: normal lab values | 1/4 Pt with biopsy-proven interstitial nephritis | Pt 1: topical and systemic steroid Pt 2: systemic steroid and oral methotrexate Pt 3: oral steroid, switched to methotrexate Pt 4: topical steroid, mydriatic, subsequently oral steroid | Regular follow-up for up to 3 years | Chorioretinal lesions should be recognized as a component of TINU |
Hettinga et al. (2015), Netherlands [41] | 8 | Two definite and six probable TINU cases, aged 12–20 years. | All PT had increased serum creatinine values, 7/8 Pt had increased urinary β-2 microglobulin levels | 2/8 with biopsy-proven AIN | NA | NA | Urinary β-2 microglobulin and serum creatinine are a simple diagnostic screening tool for detecting renal dysfunction in TINU |
Legendre et al. (2016), France [42] | 41 | 25 females and 16 males with biopsy-proven TINU. Median age at disease onset 46.8 years. 29/41 Pt had a bilateral anterior uveitis, and 24/41 presented with deterioration in general health | Moderate proteinuria in 32/41 Pt, sterile leukocyturia in 25/36 Pt. Median estimated GFR was 27 ml/minute per 1.73 m2 | All Pt had AIN, 19/39 with light-to-moderate fibrosis and 5 Pt with acute tubular necrosis | 36/41 Pt treated with oral corticosteroids, median duration of 8.0 months. | After 1 year of follow-up, 32% of patients suffered from moderate-to-severe chronic kidney disease, and 40% of Pt had uveitis relapses | Use of oral corticosteroids in TINU was associated with fewer uveitis relapses, but not better kidney function |
Sobolewska et al. (2016), Germany [28] | 9 | Five female and four male Pt mean age 16.7 years. All presented with bilateral uveitis | Elevated urinary β-2 microglobulin levels in 8/9 Pt | 3 Pt with biopsy-proven AIN. In 2 pediatric cases, parents declined renal biopsy | Mean follow-up of 19.6 months. 1 Pt with recurrences after 133 months of treatment | Mean follow-up period was 54.8 years | TINU syndrome characterized by limited responsiveness to corticosteroid therapy and less by severe complications |
Sawai et al. (2016), Japan [43] | 2 | Two 14-year-old girls. Pt 1 had systemic symptoms and low back pain 4 days after third dose of HPV vaccination. Pt 2 had anterior uveitis 10 weeks after third dose of HPV vaccine | Pt 1: elevated CRP, serum creatinine, leukocyturia, glycosuria, and proteinuria Pt 2: elevated serum creatinine, glycosuria, proteinuria, hematuria | Renal biopsy-proven AIN in 1/2 Pt | Topical and systemic steroid in both cases | Pt 1 has stable renal function and long-term topical steroid therapy for uveitis. Pt 2 without symptoms after steroid therapy cessation | HPV vaccine might be causally related to TINU syndrome |
Ariba et al. (2017), Tunisia [44] | 4 | Two male and two female patients aged 41–70 years. 1/4 Pt had fever, 3/4 Pt weight loss | Acute renal injury in 4/4 Pt. ESR elevated in all Pt, CRP in 3/4 Pt. ANCA positive 1:80 in 1/4 Pt | Renal biopsy performed in 1 Pt, consistent with AIN, without interstitial fibrosis | All patients initially received topical steroids. Systemic steroid started at onset of renal symptoms with tapering over 5-month period. | Renal outcome favorable in all Pt | The presentation and recognition of TINU in adult patients is probably underestimated |
Nagashima et al. (2017), Japan [45] | 3 | Pt 1: 15-year-old boy with bilateral anterior uveitis Pt 2: 14-year-old girl with bilateral papilledema Pt 3: 49-year-old woman with panuveitis | Pt 1: elevated IgG, elevated ESR and CRP, azotemia, elevated urinary β2 microglobulin and NAG Pt 2: normal at initial visit Pt 3: mild increase in serum creatinine | Pt 1: biopsy-proven AIN Pt 2: no biopsy approach Pt 3: biopsy-proven AIN 12 months before admission | Pt 1: pulse of methylprednisolone 1 g/day for 3 days, tapering of dose Pt 2: topical steroid, triamcinolone acetonide Pt 3: topical and systemic steroid | Pt 1: continued topical and oral steroids needed due to relapse Pt 2: no relapse Pt 3: no relapse | In addition to anterior uveitis, TINU may present also with fundal features |
Jia et al. (2018), People’s Republic of China [22] | 38 | NA | NA | All Pt with clinicopathologically diagnosed AIN | NA | NA | Patients with drug-induced AIN or TINU have genetic susceptibility in HLA-DQA1, -DQB1, and DRB1 alleles |
Provencher et al. (2018), Iowa [46] | 9 | 9 TINU Pt with iridocyclitis and elevated urinary β-2-microglobulin, 9/9 met full diagnostic criteria | Mean urinary β-2 microglobulin at presentation was 6536 μg/L (40.9 times the upper limit of normal); elevated serum creatinine in 7/9 Pt; proteinuria in 5/9 Pt | Performed in 3/9 Pt. All biopsies showed acute TIN | All Pt were treated with topical steroids, and oral steroids were used in 8/9 Pt. Two Pt were also treated with mycophenolate mofetil | Mean follow-up was 36.2 months. Relapse occurred once in two different Pt. An exacerbation occurred in 7/9 Pt within the first year | Urinary β-2 microglobulin correlates with uveitis activity and trends down over the course of TINU |
Kanno et al. (2018), Japan [47] | 5 | Two male and three female Pt; mean age of 15.8 years. First presentation to ophthalmology in 4/5 Pt, pediatrics 1/5 Pt | Serum creatinine slightly increased in 2/5 Pt. Proteinuria in 3/5 Pt, glycosuria in 4/5 Pt, elevated urinary β-2-microglobulin in all Pt | 2/5 Pt underwent renal biopsy, showing focal AIN | All Pt received topical steroids, 3/5 needed also systemic steroid because of renal manifestations | Mean follow-up of 54.0 months. Two Pt had recurrence of nephritis after steroid tapering. One Pt developed ocular hypertension on steroid therapy. Recurrence-free periods ranged from 12 to 71 months | Urinary β2 microglobulin level and HLA typing (especially HLA-DR4 or DRB1) may help in the diagnosis of TINU |
Zhang et al. (2018), People’s Republic of China [48] | 4 | Age 10.8–13.6 years | All Pt presented with proteinuria and elevated urinary α-1-microglobulin. The ratio of urinary α1-microglobulin to microalbumin was greater than 1 | NA | NA | All Pt seen within a 3-year period | A ratio of urinary α1-microglobulin to microalbumin greater than 1 can be used as a diagnostic criterion for tubuloproteinuria |
Pereira et al. (2018), Portugal [49] | 3 | Pt 1: 13-year-old female presenting with bilateral anterior uveitis Pt 2: 12-year-old female presenting with bilateral and intermediate uveitis Pt 3: 12-year-old female presenting with systemic symptoms | Pt 1: hypertension, raised inflammatory markers, decreased GFR, hypokalemia, metabolic acidosis, leukocyturia, glucosuria, hematuria, non-nephrotic proteinuria, and raised urine β2-microglobulin levels Pt 2: iron-deficiency anemia, elevated ESR, decreased GFR, leukocyturia, glucosuria, hematuria, and non-nephrotic proteinuria Pt 3: decreased GFR, leukocyturia, glucosuria, hematuria, non-nephrotic proteinuria, and raised urine β-2-microglobulin levels | Pt 1: diffuse mononuclear cell interstitial infiltrates, consistent with AIN Pt 2: no biopsy Pt 3: lymphoplasmacytic interstitial infiltrates consistent with AIN | Pt 1: ocular dexamethasone and mydriatics, oral prednisolone, amlodipine, and potassium citrate. Afterwards methotrexate Pt 2: mydriatics, topical corticosteroids, and oral deflazacort Pt 3: ocular and systemic corticosteroids, mydriatics, and methotrexate | Pt 1: 5 years follow-up Pt 2: at 18 months receiving methotrexate, on remission Pt 3: one episode of recurrent uveitis within 5 months observation period | Patients with uveitis need to be screened for renal disease |
Yang et al. (2019), People’s Republic of China [30] | 32 | Female-to-male ratio was 1.46, mean age of onset 41.1 years. 20/32 Pt had uveitis after AIN. Fatigue was most common systemic symptom (30/32 Pt) and polyuria most common renal symptom (20/32 Pt) | 2/32 Pt had anemia. Other laboratory data are NA | Diagnoses of AIN were all confirmed by renal biopsy | Topical and systemic steroids in all Pt, from 2 to 38 months. Immunomodulatory agents administered to 18/32 Pt | Mean duration of follow-up was 3.16 years. 50% of recurrences occurred during the first year | Ultra-wide-field fluorescence is sensitive in detecting the activity of uveitis and might be useful in monitoring disease progression |
Takeuchi et al. (2019), Japan [50] | 8 | Eight TINU Pt within a cohort of 156 Pt with noninfectious uveitis | NA | NA | Topical steroid monotherapy in 6/8 Pt, other 2 Pt received long-term steroids | NA | Betamethasone eye drops, topical triamcinolone acetonide, and long-term, systemic corticosteroids were the major therapeutic strategies used for uveitis relapse or exacerbation |
Abd et al. (2020), Egypt [51] | 8 | Eight TINU Pt within a cohort of 781 Pt with intermediate uveitis | NA | NA | NA | NA | 40% of patients with intermediate uveitis had identifiable a systemic disease |
Clave et al. (2019), France [25] | 7 | Five male and two female Pt, aged 10.1–14.5 years, all with bilateral uveitis and renal involvement | All Pt with elevated serum creatinine and lower GFR, other laboratory data NA | NA | Full-dose steroid treatment was maintained for 1 month in all Pt, followed by gradual tapering. Steroid treatment was continued for 6.0 months | All Pt showed a gradual improvement of renal function | Children with idiopathic AIN and prompt treatment have a better prognosis, and chronic kidney disease occurrence justifies long-term follow-up |
Çakan et al. (2019), Turkey [52] | 4 | Three male and one female Pt, median age at diagnosis of uveitis 13.4 years. Bilateral anterior uveitis in 3/4 Pt. All had systemic manifestations | All Pt had renal manifestations as microscopic hematuria, glycosuria, and mild proteinuria | NA | All Pt received topical steroids, and 1 Pt needed systemic steroids and methotrexate. | NA | A simple urine test may help in establishing the diagnosis of TINU syndrome in uveitis patients |
Cao et al. (2020), Ohio [53] | 10 | Six female and four male Pt with TINU and posterior ocular segment inflammation. Age distribution was bimodal (10–46 years and 77–83 years) | Mean urinary β-2-microglobulin levels were more than tenfold upper limit of normal. Serum creatinine was elevated in 6/10 Pt. Urinalysis was abnormal in 9/10 Pt | 2/10 Pt underwent a renal biopsy, one of which was positive for moderate-to-severe acute AIN, consistent with TINU | 11 of 20 eyes were initially treated with topical steroids only, and 2 Pt received oral steroids alone due to posterior segment involvement | Visual acuity was stable or improved for all but one patient who had a subretinal macular scar | Posterior segment inflammation in the setting of TINU is not uncommon |
Roy et al. (2020), United Kingdom [54] | 6 | 6 Pt from a cohort of 10 Pt with AIN, age range 6–16 years, male-to-female ratio 1:9 | Lowest GFR in TINU Pt ranged from 7 to 30 ml/min/1.73 m2 | All Pt had biopsy-proven AIN | All Pt received systemic steroid therapy | Latest follow-up was from 2 to 70 months. None had experienced a recurrence of AIN | There is a high proportion of TINU in a UK case series of biopsy-proven AIN in children |
Kitano et al. (2020), Japan [55] | 4 | 4 Pt with TINU from a cohort of 98 Japanese uveitis Pt | NA | NA | 48% of the 98 Pt received only topical steroids, whereas 39/98 Pt received some form of systemic antiinflammatory therapy | 80.9% of the eyes maintained a visual acuity of 20/20 at the final visit | Hypotony, serous retinal detachment, and pupil disorders can lead to visual loss in uveitis patients, including TINU |
Total | 306 |