Filipa Silva*, Sofia O Correia, Ana Castro, Carla Moreira, Sofia Santos, Jorge Malheiro, Josefina Santos, La Salete Martins and António CabritaNephrology Department, Centro Hospitalar e Universitário do Porto, Porto, Portugal
*Address for Correspondence: Filipa Silva, Nephrology Department, Centro Hospitalar e Universitário do Porto, Porto, Portugal. Email: firstname.lastname@example.org
Dates: Submitted: 05 January 2018; Approved: 08 March 2018; Published: 09 March 2018
How to cite this article: Silva F, Correia SO, Castro A, Moreira C, Santos S, et al. Acute Tubulointersticial Nephritis with Uveitis: A report of two cases. J Clini Nephrol. 2018; 2: 008-014. DOI: 10.29328/journal.jcn.1001012
Copyright: © 2018 Silva F, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Tubulointersticial nephritis; Anterior uveitis; Glucocorticoids; Renal dysfunction
Tubulointersticial nephritis and uveitis syndrome is an idiopathic and rare cause of acute kidney injury but it should not overlooked because it usually requires specific therapeutic interventions.
We report two distinct cases; one in a young and other in an elder female. Both cases presented with unspecific constitutional symptoms but had different onset of renal and ocular involvement. Both were treated with topical and systemic corticoids: although a good initial response in both cases, an early relapse after steroids taper was observed in the younger patient and a persistent of renal dysfunction was seen in the older one.
The underling mechanisms of TINU syndrome are still unclear. The correct diagnosis can be difficult to establish especially when the renal involvement is mild. The exclusion of other systemic diseases is mandatory and the ophthalmological evaluation plays an important role in the presence of an interstitial nephritis with no defined etiology. Recent data associate a worse renal prognosis when the disease appears in advanced age, although we do not yet have data on the follow-up of these patients in the long term.
A high clinical suspicion and understanding of this disease is necessary for an adequate management and treatment of these patients. In both of our cases the outcome was good but we have a short follow-up. The histological presentation of this disease in our older patient was similar from that reported in the literature, with a high percentage of fibrosis and chronicity of renal tissue that can contribute for the higher grade of renal dysfunction.
Tubulointersticial nephritis and uveitis (TINU) syndrome is defined by the combination of idiopathic acute tubulointersticial nephritis (AIN) and uveitis. It was described for the first time in 1975 by Dobrin et al. , and more than 250 cases have now been reported, mostly in children and young females [2,3]. No identifiable risk factors have been found in at least 50 percent of cases [3,4]. In some of them, prior infections and/or use of specific drugs have been implicated [3-5]. There is no particular affinity with race, familiar inheritance, genetics or geographic clusters .
We report two different cases of TINU syndrome, one in an old and other in a young female. Although they had similar constitutional symptoms at presentation, the renal and ocular manifestations as well as the response to treatment was distinct.
A 71-year-old female with an unremarkable past medical history: no chronic medication nor recent use of nonsteroidal anti-inflammatory drugs (AINEs); no history of tobacco or alcohol. She presented with weight loss, fatigue, asthenia and malaise in the previous 4 months. No other symptoms were reported. At hospital admission she presented with an elevated C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), 74mm. Blood samples showed new onset of normocytic, normochromic (NN) anemia (haemoglobin of 9,3g/dL) and acute renal failure KDIGO 1 (serum creatinine (sCr) increased from 0,9mg/dL to 3,1mg/dL). Urinalysis showed proteinuria (ratio proteinurine/creatinineurine 1,2g/g), glycosuria (>1000mg/dL) and granular cats (10-25/field). No eosinophiluria nor eosinophilia. No abnormalities in the renal ultrasound were observed. Antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), anti-double-stranded DNA (anti-dsDNA), HLA-B27, anti-RNP/Smith, SSA, SSB, SCL70, and antoJo1 antibodies were negative. Angiotensin converting enzyme (ECA) and serology for syphilis were negative too. In renal biopsy two of the twenty-six glomeruli identified had global sclerosis. Interstitial with intense inflammatory infiltrate of lymphocyte predominance occupying 25% of cortical extension. Was noticeable with fibrosis in 30 to 40%. Renal tubules appeared with thickened basement membrane, and focal lesions of neutrophilic tubulitis and tubular atrophy in 30 to 40% were detectable. Arterial branches and arterioles had discrete intima myofibroblastic thickening. Immunofluorescence study with antibodies to albumin, C3, C4, C1q, IgA, IgG, IgM, kappa and lambda chains revealed absence of immune deposits. Immunohistochemical study was compatible with lymphocyte population composed mainly by T lymphocytes. She had no ocular symptoms but evidence of bilateral anterior uveitis was present on ocular examination. Prednisolone, 1mg/Kg/day, was initiated with early recover of renal function. She started steroids taper after 3 months and they were stopped after completing 5 months (sCr of 1,4mg/dL). After 10 months of follow-up she had no anemia (Hb of 12,9g/dL), low VS (10mm), sCr of 1,4mg/dL and no signs of tubular dysfunction (ratio proteinurine/creatinineurine 0,3g/g), no glycosuria (100mg/dL) and granular cats (0-2/field) [Figure 1].
A 18-year-old female with recent diagnosis of hyperthyroidism. No past surgical history, no tobacco or alcohol, no recreational drug abuse. Occasional consumption of AINEs. She presented with photophobia for 9 months and antibiotics were given for suspicious of bilateral purulent conjunctivitis. Two months before admission started with complaints of weight loss, vomits, abdominal pain, diarrhea, fatigue and anorexia. Blood samples showed anemia and altered renal function with sCr of 1.8mg/dL, hypouricemia and hypophosphatemia. Presence of glycosuria, granular casts and proteinuria (<1g/per day) was apparent in the urinalysis. Renal ultrasonography was normal as well as immunological markers (ANA, ANCA, anti-dsDNA, HLA-B27, anti-RNP/Smith, SSA, SSB, SCL70, and antoJo1). Negative ECA and VDRL. Kidney biopsy revealed mesangial expansion without mesangial hyper-cellularity and thickening of Bowman´s capsule. Extensive inflammatory infiltrate of lymphoplasmocytic predominance occupying more than 25% of the extension of the cortex was observed, besides fibrosis in approximately 5 to 10% of the cortical extension and degenerative and regenerative aspects of tubular epithelium. Tubular atrophy was present in 10% of the extent of the cortex. Arterial branches and arterioles had concentric wall thickening. The direct immunofluorescence study with antibodies to albumin, C3, C4, C1q, IgA, IgG and IgM showed vestigial mesangial and focal tubular membrane C3 with absence of deposits for the remaining antibodies tested. Electron microscopy without ultrastructural changes.
Ophthalmologic evaluation documented bilateral anterior uveitis. She started corticoid therapy, ocular and systemic (prednisolone 1mg/Kg/day) with early recovered of renal function. She had recurrent uveitis when steroids taper was done (after 3 months) with 2 episodes of recurrent uveitis, the last one with necessity of systemic corticotherapy (completing 1 year of prednisolone). After 2 years she maintains normal renal function (sCr of 1mg/dL) and no signs of tubular dysfunction (ratio proteinurine/creatinineurine 0,1g/g), no glicosuria (0mg/dL) nor granular cats (0-2/field) [Figure 2 and Table].
TINU syndrome is a rare disease with an acute onset characterized by ocular and renal involvement . The underlying mechanism of TINU remains unclear. Some studies suggest that IgG antibodies directed to modified CRP, an autoantigen common to both renal tubular cells and uvea may be implied in the pathogenesis, since they are significantly higher in TINU patients when compared with patients with other diseases (Sjogren syndrome, drug-induced interstitial nephritis, glomerulonephritis, IgA nephropathy, minimal change disease, ANCA associated vasculitis and amyloidosis) or healthy controls .
Gafter et al., associated TINU syndrome to suppression of cell-mediated immunity and reported normal T-cell population but decreased secretion of lymphokines and anergy to skin tests in these patients. This paradox is not unique to TINU, as the presence of increased tissue inflammation with concomitant suppression of peripheral immunity is also seen in patients with sarcoidosis [7,8]. Other studies reported a genetic association with HLA-DQA1*01, HLADQB1*05 and HLA-DQB1*01 [3,5]. There has also been reported TINU syndrome in patients with autoimmune disease like hypoparathyroidism, thyroid disease, immunoglobulin G4 related autoimmune disease and rheumatoid arthritis [3,6,9-11].
Estimated prevalence is around 3,5 cases/millions of persons and the incidence is 0,2 cases/million/year [12,13]. Most patients are adolescents and young women with a median age of 15 years  although it has also been reported in older adults [4,15], like one case herein reported. Likewise, there is a female predominance in all series [3,4]. TINU may present with unspecific general symptoms including fever, weight loss, asthenia, fatigue, anorexia, abdominal and flank pain, myalgias, arthralgias, headache between another [4,13,16,17]. In our cases both patients presented with constitutional symptoms.
The typical ocular presentation of TINU syndrome is bilateral and nongranulomatous anterior uveitis with sudden onset in 80% of patients, but may also manifest as posterior or panuveitis [4,18]. Ocular symptoms include eye redness and pain, photophobia and decreased visual acuity. Ocular physical exam findings include anterior chamber cell and flare, keratic precipitates and redness .
Renal manifestations include flank pain, sterile pyuria, proteinuria, hematuria and acute kidney injury. Proximal and distal tubular defects can be commonly seen resulting in aminoaciduria, glycosuria, phosphaturia and acidifications defects [20,21]. Nephritis precedes uveitis in 65%, in 21% uveitis is present before nephritis and in 15% the two occur in simultaneously . In our report, one patient presented first with renal involvement and the other with ocular disease.
There are no specific serum markers or laboratory findings that suggest TINU. We may find leucocyturia, eosinophilia, anemia, slightly abnormal liver functions test and an elevated ESR and CRP . Beta 2 microglobulin and Krebs von den Lunge-6 (KL-6) could be two potential diagnostic markers according to some reports. Urinary Beta 2 microglobulin is a marker of interstitial nephritis and not only was markedly elevated in almost every case tested, but also, remains elevated for months. This test was not performed in our patients. Takemura et al. showed a correlation between beta-2-microglobulin levels and the histologic grade of tubulointersticial nephritis in 10 children . KL-6 is a glycoprotein present in the lung tissue. Compared with patients with uveitis from other causes, serum KL-6 levels were significantly elevated in patients with TINU syndrome. On renal biopsy, stained strongly with anti KL-6 antibody suggesting that the elevated KL-6 levels reflect the underlying renal lesion . However, KL-6 levels were not different between patients with TINU syndrome and drug-induced interstitial nephritis . Some report an association of TINU with a variety of immunological markers like ANA, autoantibody directed against renal tubular cells, rheumatoid factor and hypocomplementemia [24-27].
TINU syndrome might be underdiagnosed due to lack of recognition . The definitive diagnosis is nonspecific and is suggested by combination of renal involvement and uveitis with renal biopsy consistent with AIN. On light microscopy, typical biopsy findings include tubulointersticial edema and infiltration of inflammatory cells composed mainly of mononuclear cells. Glomerular and vascular structures are generally preserved. There are no specific findings with immunofluorescence and electron microscopy .
In our cases, all kidneys biopsies had inflammatory infiltrate with lymphocyte predominance. No alterations on immunofluorescence or electronic microscopy were found. The older patient presented with more fibrosis and tubular atrophy traducing a worse outcome when compared with the younger patients, who had less signs of chronicity on biopsy.
In 2001 Mandeville et al., were the only group to report evaluation criteria for the diagnosis of TINU syndrome. According to them, besides the presence of AIN and uveitis without no sign of other systemic disease, one of the following criteria should be present: abnormal renal function, abnormal urinalysis and systemic symptoms with more than three weeks .
There are some disorders that should be considered for the differential diagnosis of AIN occurring in association with ocular findings. They include sarcoidosis, Sjogren’s syndrome, Wegener’s granulomatosis, systemic lupus erythematous, Behcet’s disease, hyperthyroidism, primary hyperparathyroidism and infectious diseases (tuberculosis, brucellosis, toxoplasmosis and histoplasmosis). Sarcoidosis and Sjogren syndrome share similar findings with TINU, making accurate diagnosis difficult in the absence of characteristic involvement of other organs. Treatment is not yet standardized and varies between centers and clinicians .
Topical corticosteroids are recommended as the first choice treatment in anterior uveitis . However, 80% of patients requires systemic corticosteroids and 9% progress to other immunosuppressive treatment . Some studies reported that local and/or systemic corticosteroids are not sufficient to prevent recurrences of uveitis in 78% and 71%, respectively  and other immunosuppressive drugs may be necessary to prevent relapses . Sobolewska et al. suggested that treatment duration of at least 12 months with oral systemic corticosteroids or immunomodulatory agents may reduce or prevent the recurrence rate in patients who relapse . In our cases, the elder patient recovered with topical and systemic corticosteroids, but the younger one had a relapse of uveitis after systemic corticoterapy tapering. Until now, none of them started any additional immunosuppressive drugs.
AIN can resolve spontaneously. Nevertheless, in cases with progressive renal impairment, oral prednisolone, started at 1mg/kg/day, is usually recommended . Therapy is given by three to six months depending upon the response and then is slowly tapered. Dialysis therapy is not usually required. In our cases we started tapering corticoterapy after 3 months and stopped after 5.
Whereas eye symptoms tended to recur (40% of patients at 1 year of follow-up), renal symptoms rarely do so (9% of patients). In contrast, progression to chronic disease was rare for eye symptoms (14% at 1 year) and more frequent for renal symptoms (69% at 1year) [3,4,19,29]. The long term prognosis isn’t well established since there are few data with long follow-up. While the most reports described TINU syndrome as having a favorable renal outcome [4,19,22,31] other data suggests that full renal recovery is not the norm evolving to impaired renal function in the medium term [3,29].
Legendre et al., recently report new data suggesting that the older the patient is, the poorer was the renal prognosis after 1 year of follow-up. This difference could in part be explained by the tendency for accelerated fibrosis in the older patients . Besides, they also associated the initially severity of renal symptoms with the renal function after 1 year of follow-up. This data was in accordance with our cases in which the older patient presented with a higher grade of renal dysfunction, more fibrosis in renal biopsy and progressed to chronic renal dysfunction. Until now, no pathological markers proved to be prognostic factors in TINU syndrome [3,4].
TINU syndrome is a rare disease and it may be difficult to recognize. Patients that have acute interstitial nephritis on renal biopsy and have no obvious underlying cause may require a slit lamp examination to exclude uveitis.
This disease should be considered in the differential diagnosis of tubulointersticial nephritis of unclear etiology, especially in the presence of ocular manifestations, in older patients were the disease is probably underdiagnosed, and in young patients with asymptomatic mild renal disease.
The long-term care is fundamental given the possible evolution with impaired renal function, especially in elder people.
- Dobrin RS, Vernier RL, Fish AL. Acute eosinophilic interstitial nephritis and renal failure with bone marrow-lymph node granulomas and anterior uveitis. A new syndrome. Am J Med. 1975; 59: 325. Ref.: https://goo.gl/dJqD1n
- Abed L, Merouani A, Haddad E, Benoit G, Oligny LL, et al. Presence of autoantibodies against tubular and uveal cells in a patient with tubulointerstitial nephritis and uveitis (TINU) syndrome. Nephrol Dial Transplant. 2008; 23: 1452-1455. Ref.: https://goo.gl/QDSWdQ
- Li C, Su T, Chu R, Li X, Yang L. Tubulointerstitial nephritis with uveitis in Chinese adults. Clin J Am Soc Nephrol. 2014; 9: 21-28. Ref.: https://goo.gl/Cu8yBw
- Mandeville JT, Levinson RD, Holland GN. The tubulointerstitial nephritis and uveitis syndrome. Surv Ophthalmol. 2001; 46: 195-208. Ref.: https://goo.gl/1nckef
- Levinson RD, Park MS, Rikkers SM, Reed EF, Smith JR, et al. Strong associations between specific HLA-DQ and HLA-DR alleles and the tubulointerstitial nephritis and uveitis syndrome. Invest Ophthalmol Vis Sci. 2003; 44: 653-657. Ref.: https://goo.gl/u7iZ2y
- Tan Y, Yu F, Qu Z, Su T, Xing GQ, et al. Modified C-reactive protein might be a target autoantigen of TINU syndrome. Clin J Am Soc Nephrol. 2011; 6: 93-100. Ref.: https://goo.gl/Jf8hbb
- Gafter U, Kalechman Y, Zevin D, Korzets A, Livni E, et al. Tubulointerstitial nephritis and uveitis: association with suppressed cellular immunity. Nephrol Dial Transplant. 1993; 8: 821-826. Ref.: https://goo.gl/H3nB7X
- Yoshioka K, Takemura T, Kanasaki M, Akano N, Maki S. Acute interstitial nephritis and uveitis syndrome: activated immune cell infiltration in the kidney. Pediatr Nephrol. 1991; 5: 232-234. Ref.: https://goo.gl/91Xzt5
- Catalano C, Harris PE, Enia G, Postorino M, Martorano C, et al. Acute interstitial nephritis associated with uveitis and primary hypoparathyroidism. Am J Kidney Dis. 1989; 14: 317-318. Ref.: https://goo.gl/1iZn4f
- Paul E, Van Why S, Carpenter TO. Hyperthyroidism: a novel feature of the tubulointerstitial nephritis and uveitis syndrome. Pediatrics. 1999; 104: 314-317. Ref.: https://goo.gl/yqBfxR
- Yoneda K, Murata K, Katayama K, Ishikawa E, Fuke H, et al. Tubulointerstitial nephritis associated with IgG4-related autoimmune disease. Am J Kidney Dis. 2007; 50: 455-462. Ref.: https://goo.gl/JmWqVb
- Helms E, Sevilla KS, Hartshorne MF, Harris A, Nichols MJ, et al. Tubulointersticial nephritis and uveitis syndrome: use of gallium scintigraphy in its diagnosis and treatment. Int Urol Nephrol. 2005; 37: 119-122. Ref.: https://goo.gl/Mw3h8y
- Weinstein O, Tovbin D, Rogachev B, Vorobiov M, Kratz A, et al. Clinical manifestations of adult tubulointerstcial nephritis and uveitis (TINU) syndrome. Int Ophthalmol. 2010; 30: 621-628. Ref.: https://goo.gl/7pVYki
- Sessa A, Meroni M, Battini G, Viganò G, Brambilla PL, et al. Acute renal failure due to idiopathic tubulo-intestinal nephritis and uveitis: "TINU syndrome". Case report and review of the literature. J Nephrol. 2000; 13: 377-380. Ref.: https://goo.gl/gmvqyJ
- Salu P, Stempels N, Vanden Houte K, Verbeelen D. Acute tubulointerstitial nephritis and uveitis syndrome in the elderly. Br J Ophthalmol. 1990; 74: 53. Ref.: https://goo.gl/4XBexw
- Jahnukainen T, Ala-Houhala M, Karikoski R, Kataja J, Saarela V, et al. Clinical outcome and occurrence of uveitis in children with idiopathic tubulointersticial nephritis. Pediatr Nephrol Berl Ger. 2011; 26: 291-299. Ref.: https://goo.gl/VbHvLV
- Han JM, Lee YJ, Woo SJ. A case of tubulointersticial nephritis and uveitis syndrome in an elderly patient. Korean J Ophthalmol. 2012; 26: 398-401. Ref.: https://goo.gl/tMzJJL
- Mackensen F, Smith JR, Rosenbaum JT: Enhanced recognition, treatment, and prognosis of tubulointersticial nephritis and uveitis syndrome. Ophthalmology. 2007; 114: 995-999. Ref.: https://goo.gl/Rwyw18
- Goda C, Kotake S, Ichiishi A, Namba K, Kitaichi N, et al. Clinical features in tubulointersticial nephritis and uveitis (TINU) syndrome. Am J Ophthalmol. 2005; 40: 637-641. Ref.: https://goo.gl/qUEY3P
- Igarashi T, Kawato H, Kamoshita S, Nosaka K, Seiya K, et al. Acute tubulointerstitial nephritis with uveitis syndrome presenting as multiple tubular dysfunction including Fanconi's syndrome. Pediatr Nephrol. 1992; 6: 547-549. Ref.: https://goo.gl/nacX4d
- Koike K, Lida S, Usui M, Matsumoto Y, Fukami K, et al. Adult-onset acute tubulointerstitial nephritis and uveitis with Fanconi syndrome. Case report and review of the literature. Clin Nephrol. 2007; 67: 255-259. Ref.: https://goo.gl/U9SGzJ
- Takemura T, Okada M, Hino S, Fukushima K, Yamamoto S, et al. Course and outcome of tubulointerstitial nephritis and uveitis syndrome. Am J Kidney Dis. 1999; 34: 1016-1021. Ref.: https://goo.gl/NqJJDw
- Parameswaran S, Mittal N, Joshi K, M. Rathi, H. S. Kohli, et al. Tubulointersticial nephritis with uveitis syndrome: A case report and review of literature. Indian J Nephrol. 2010; 20: 103-105. Ref.: https://goo.gl/NenrkF
- Simon AH, Alves-Filho G, Ribeiro-Alves MA. Acute tubulointerstitial nephritis and uveitis with antineutrophil cytoplasmic antibody. Am J Kidney Dis. 1996; 28: 124-127. Ref.: https://goo.gl/eJw2Xm
- Wakaki H, Sakamoto H, Awazu M. Tubulointerstitial nephritis and uveitis syndrome with autoantibody directed to renal tubular cells. Pediatrics. 2001; 107: 1443-1446. Ref.: https://goo.gl/rom7ew
- Conz PA, Milan M, Bragantini L, La Greca G, Bevilacqua PA. TINU syndrome associated with reduced complement levels. Nephron. 2001; 89: 340-341. Ref.: https://goo.gl/v4X5Nn
- Paladini A, Venturoli V, Mosconi G, Zambianchi L, Serra L, et al. Tubulointerstitial nephritis and uveitis syndrome in a twelve-year-old girl. Case Rep Pediatr. 2013. Ref.: https://goo.gl/ghZtWz
- Joss N, Morris S, Young B, Geddes C. Granulomatous interstitial nephritis. Clin J Am Soc Nephrol. 2007; 2: 222-230. Ref.: https://goo.gl/fybEaV
- Legendre M, Devilliers H, Perard L, Groh M, Nefti H, et al. Clinicopathologic characteristics, treatment, and outcomes of tubulointerstitial nephritis and uveitis syndrome in adults: a national retrospective strobe-compliant study. Medicine. 2016; 95: 26. Ref.: https://goo.gl/Fw3y2D
- Sobolewska B, Bayyoud T, Deuter C, Doycheva D, Zierhut M. Long-term follow up of patients with tubulointersticial nephritis and uveitis (TINU) syndrome. Ocular Immunology e Inflamation. 2016; 1-7. Ref.: https://goo.gl/jaaepK
- Kobayashi Y, Honda M, Yoshikawa N, et al. Acute tubulointersticial nephritis in 21 Japanese children. Clin Nephrol. 2000; 54: 191-197. Ref.: https://goo.gl/m4p2Mz
- Yang H-C, Fogo AB. Fibrosis and renal aging. Kidney Int Suppl. 2014; 4: 75-78. Ref.: https://goo.gl/xejBfA