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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2021  |  Volume : 32  |  Issue : 2  |  Page : 554-558
Acute tubulointerstitial nephritis in two sisters with simultaneous uveitis in one

Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

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Date of Web Publication11-Jan-2022


Tubulointerstitial nephritis uveitis syndrome (TINU) is an underdiagnosed entity, defined by association of uveitis and TIN with no evidence of concomitant systemic disease that might present with both ocular and renal manifestations. Although not common, it needs awareness and collaborations of pediatricians and ophthalmologists for prompt diagnosis and treatment. The exact pathogenesis of the disease is poorly understood, and it predominantly affects female adolescents. Since its early description at 1975, many cases have been reported but only a few were familial case reports. Herein, we report TIN in two sisters, first one with uveitis (TINU) and second one, eight years later at the same age without uveitis.

How to cite this article:
Derakhshan A, Derakhshan D. Acute tubulointerstitial nephritis in two sisters with simultaneous uveitis in one. Saudi J Kidney Dis Transpl 2021;32:554-8

How to cite this URL:
Derakhshan A, Derakhshan D. Acute tubulointerstitial nephritis in two sisters with simultaneous uveitis in one. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 May 16];32:554-8. Available from: https://www.sjkdt.org/text.asp?2021/32/2/554/335470

   Introduction Top

Acute tubulointerstitial nephritis (TIN) is a multifactorial disease with regard to pathogenesis. The most common etiologies include infections, drugs, and immunologic factors.[1],[2],[3],[4] It may also happen in the context of other systemic diseases.[5],[6],[7] TIN is considered an uncommon cause of acute kidney injury in children and is usually underdiagnosed due to the vague presenting symptoms such as fatigue, weight loss, fever, and arthralgia.[1],[2] TIN might be associated with uveitis [the so-called TIN uveitis (TINU) syndrome] at any age although it is more common in young females with a median age of presentation at 15 years.[3],[4] There are some reports of genetic predilection of TINU and its association with specific types of HLA as well as few reports regarding the occurrence of TINU in the siblings and monozygotic twins.[8],[9],[10],[11],[12] There is also a single report of TINU in a child and TIN without eye involvement in her sister.[13] Our case is the second to be reported in the literature with TINU in a 13-year-old girl and TIN without uveitis in her sibling eight years later with the same age of onset.

   Case Reports Top

Verbal consent was obtained from the father, and the patients upon their last visit with assuring them that their names are secret. Since they are available taking a written consent is possible too.

Case 1

A 13-year-old girl presented with red eyes associated with pain on palpation and eye movement and was diagnosed as anterior uveitis. Upon her laboratory tests, the ophthalmologist noticed proteinuria (2+) and glucosuria (1+) in the urine analysis and referred her to pediatric nephrologist for more evaluation on February 24, 2011. On physical examination, she was a well-nourished well-developed girl; weight: 38 kg, height: 155 cm with BP 115/75 mm Hg (normal for age and height). [Table 1] indicates her initial laboratory tests. According to the patient’s clinical presentation and laboratory results, the clinical diagnosis of TINU was made, and a kidney biopsy was performed which revealed severe mononuclear cell infiltration composed of lymphocyte with a few plasma cells, about 50% tubular atrophy, and about 50% interstitial fibrosis. Immunofluorescence study in 10 glomeruli revealed no deposition. Prednisolone was started with daily dose of 50 mg (~1.3 mg/kg/day) and in the subsequent four weeks follow-up, her serum creatinine decreased to 106 μmol/L; therefore, the steroid dosage was reduced to half dose (25 mg–0.5 mg/kg) given every other day for the following month and tapered gradually. Meanwhile, she also had regular monthly visits by ophthalmologist. Four months later when she was on 10 mg prednisolone every other day, her early morning urine protein to creatinine ratio was 0.25 mg/mg and had 6–8 WBC/HPF in the early morning urine sample without glucose and serum creatinine level was 97 μmol/L. Seven months after her first presentation, prednisolone was discontinued with an almost normal urinalysis, early morning protein to creatinine ratio ~0.17 mg/mg, and serum creatinine still being 97 μmol/L. Four months following discontinuation of the steroid (about 1 year after the onset of her uveitis on August 2, 2011, while her serum creatinine was 88.4 μmol/L and she had normal urinalysis, she had recurrence of uveitis. At this point, mycophenolate mofetil (MMF) 500 mg, twice daily was prescribed by the ophthalmologist. On October 10, 2012, MMF dose was tapered to 500 mg once daily and her eye examination was normal. Eventually, MMF was discontinued on August 27, 2014 after about three years. Meanwhile, her urinalysis remained normal and her latest serum creatinine was 79.6 μmol/L. At the most recent follow-up session, she was doing well without recurrence.
Table 1: Initial laboratory result of case 1.

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Case 2 (The sister)

On February 18, 2018, about eight years later, her 13-year-old sister (at the same age of onset) presented with anorexia, easy fatigability, low grade fever, polyuria, and weight loss. Past medical history was negative for using any medication or nephrotoxic substances. In physical examinations, she looked pale but blood pressure and growth indices were appropriate for her age. Initial lab results are given in [Table 2]. Considering the clinical presentation, laboratory results, and positive history of TINU in her sibling, a kidney biopsy was done which revealed severe TIN with almost the same findings as her sister. Eye examinations by two different ophthalmologists were reported as entirely normal. She was treated with prednisolone 30 mg daily (1 mg/kg/day) and after about three weeks her serum creatinine declined to 78 mg/dL but still had 2+ glucose in urine analysis and early morning urine protein to creatinine ratio was 0.68 mg/mg. About seven weeks later, erythrocyte sedimentation rate was 10 mm/h, creatinine: 79 μmol/L, still had 1+ glucose in urine, and early morning urine protein to creatinine ratio declined to 0.34 mg/mg. At this time prednisolone was tapered to 10 mg every other day, MMF was added and continued for six months while prednisolone was tapered gradually and discontinued, before discontinuation of MMF. Periodic reassessments were made and in her last follow-up session on December 23, 2019 had normal urinalysis with specific gravity of 1.022, BUN 3.6 mmol/L, creatinine 79 μmol/L and eye examination was still normal as well.
Table 2: Initial laboratory result of case 2.

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   Discussion Top

Acute TIN is an inflammatory process affecting the renal tubules and interstitium. The main possible etiologies include medications, infections, immunologic diseases but the majority is from drugs of various groups including anticonvulsants, antibiotics, diuretics and nonsteroidal anti-inflammatory drugs.[1],[2],[3],[4]

The combination of TIN and uveitis, the so called TINU syndrome, was first described at 1975.[14] The disease is assumed to be rare and accounts for 2% of all cases of uveitis but represents one-third of young patients (age under 20 years) with acute onset bilateral anterior uveitis. It was thought to be more prevalent in females (female-to-male ratio 3:1)[3] but recent reviews revealed that gender is no longer a predisposing factor.[15] Although TINU is believed to have an autoimmune background, the exact pathogenesis is still not clear,[3],[14],[15] the predominance of T helper cells in renal tissue on immunohistochemistry implies the role of T-cell-mediated immunity in the pathogenesis.[12] There are evidences of HLA antigen-related genetic predilection with the occurrence of TINU and there are reports of TINU in identical twins and siblings and also a single report in a mother and her son.[10],[11],[12],[16] There are only a few reports of TINU in the siblings in the written literature, but it is possible that they may not have been reported.

Even though a diagnostic criterion was proposed in 2001 upon study on 133 cases of TINU[17], the clinical diagnosis has gained more acceptance among physicians.[15] The clinical diagnosis is made regarding the co-occurrence of uveitis with TIN which is documented by kidney biopsy and exclusion of systemic diseases such as sarcoidosis, Sjogren syndrome, and systemic lupus erythematous.[3],[14],[15] The ocular symptoms may proceed the renal symptoms in 20% of cases, but most of the times the uveitis occurs following the TIN.[3],[14] One of our cases presented with uveitis at first but had asymptomatic kidney involvement at the same time, but the other one had mainly renal findings at presentation and following corticosteroid therapy, she had no episodes of uveitis in 2-year follow-up.

Despite encountering cases of TINU in personal experience, there are only two case reports from our country, and it seems this is obviously underreported.[14],[18] Our report is the second report to the Morino et al[13] of TIN in two siblings (sisters). Interestingly, our both patients presented at the same age with two different clinical presentations.

The recommended treatment is corticosteroid therapy (1 mg/kg/day of prednisolone) in the acute phase of the disease which induces dramatic improvement in both renal and ocular symptoms but up to 50% of cases experience ocular relapse after discontinuation of steroid therapy,[3],[4],[14],[15],[17] and the relapses tend to be more severe than the first presentation. In order to prevent relapses after steroid withdrawal and adverse effects of corticosteroid, addition of immunemodulating therapy should be considered mainly in patients with chronic uveitis.[15] We also treated our both patients with steroid and then MMF with complete clinical recovery without recurrence in 10- and 2-year follow-up, respectively. Since they had clinical recovery (normal urine specific gravity and acceptable serum creatinine), re-kidney biopsy was not performed.

Despite the fact that both ocular and renal involvements have generally good long-term outcomes, uveitis has a more relapsing course and chronic uveitis is more prevalent in youngers.[3],[15] Of our two cases, one had relapse of uveitis four months after discontinuation of steroid and fortunately had no more relapse since initiating treatment with MMF and gradual discontinuation of treatment thereafter.

The major limitation to our report is a lack of measurement of urinary β2 microglobulin, but our both patients underwent kidney biopsy which is the gold standard for diagnosis of TIN and other possible differential diagnosis were excluded with serologic studies and serum complement measurements. Regarding the occurrence of the disease in sisters, the possibility of HLA predisposition is probable in our cases and lack of HLA study is another limitation to our report. On the subject of treatment, we also believe that, due to the low prevalence and lack of specific treatment protocols, we might have over treated our cases.

In conclusion, TINU should be considered in the daily practice in the field of pediatric nephrology and ophthalmology and as the ocular manifestations might occur within one month before to three months after renal involvement, collaboration of nephrologists, and ophthalmologists and follow-up of the patients is mandatory in cases of acute TIN and uveitis, respectively.

Conflict of interest: None declared.

   References Top

Lewington AJ. Acute Tubulointertstitial nephritis. In: Barratt J, Harris K, Topham P, editors. Oxford Desk Reference Nephrology. Oxford: Oxford University Press; 2009. p. 344-7.  Back to cited text no. 1
Roy S, Awogbemi T, Holt RC. Acute tubulo-interstitial nephritis in children – A retrospective case series in a UK tertiary paediatric centre. BMC Nephrol 2020;21:17.  Back to cited text no. 2
Joyce E, Glasner P, Ranganathan S, Swiatecka- Urban A. Tubulointerstitial nephritis: Diagnosis, treatment, and monitoring. Pediatr Nephrol 2017;32:577-87.  Back to cited text no. 3
Clive DM, Vanguri VK. The syndrome of tubulointerstitial nephritis with uveitis (TINU). Am J Kidney Dis 2018;72:118-28.  Back to cited text no. 4
Pagni F, Galimberti S, Galbiati E, et al. Tubulointerstitial lesions in lupus nephritis: International multicentre study in a large cohort of patients with repeat biopsy. Nephrology (Carlton) 2016;21:35-45.  Back to cited text no. 5
Lan-Ting H, You-Ming C, Li-Xin W, Chen W, Xiao-Yan Z, Hong-Yan H. Clinicopathological factors for tubulointerstitial injury in lupus nephritis. Clin Rheumatol 2020;39:1617-26.  Back to cited text no. 6
Sen ES, Ramanan AV. Juvenile idiopathic arthritis-associated uveitis. Best Pract Res Clin Rheumatol 2017;31:517-34.  Back to cited text no. 7
Reddy AK, Hwang YS, Mandelcorn ED, Davis JL. HLA-DR, DQ class II DNA typing in pediatric panuveitis and tubulointerstitial nephritis and uveitis. Am J Ophthalmol 2014; 157:678-86.e1.  Back to cited text no. 8
Mackensen F, David F, Schwenger V, et al. HLA-DRB1*0102 is associated with TINU syndrome and bilateral, sudden-onset anterior uveitis but not with interstitial nephritis alone. Br J Ophthalmol 2011;95:971-5.  Back to cited text no. 9
Biester S, Müller C, Deuter CM, Doycheva D, Altpeter E, Zierhut M. Tubulointerstitial nephritis and uveitis in siblings. Ocul Immunol Inflamm 2010;18:370-2.  Back to cited text no. 10
Howarth L, Gilbert RD, Bass P, Deshpande PV. Tubulointerstitial nephritis and uveitis in monozygotic twin boys. Pediatr Nephrol 2004; 19:917-9.  Back to cited text no. 11
Tanaka H, Waga S, Nakahata T, et al. Tubulo-interstitial nephritis and uveitis syndrome in two siblings. Tohoku J Exp Med 2001;194:71- 4.  Back to cited text no. 12
Morino M, Inami K, Kobayashi T, Yanagisawa K, Maeda K. Acute tubulointerstitial nephritis in two siblings and concomitant uveitis in one. Acta Paediatr Jpn 1991;33:93-8.  Back to cited text no. 13
Savaj S, Asgari M. Tubulointerstitial nephritis and uveitis: Report of a rare syndrome. Iran J Kidney Dis 2011;5:66-8.  Back to cited text no. 14
Pakzad-Vaezi K, Pepple KL. Tubulointerstitial nephritis and uveitis. Curr Opin Ophthalmol 2017;28:629-35.  Back to cited text no. 15
Dusek J, Urbanova I, Stejskal J, Seeman T, Vondrak K, Janda J. Tubulointerstitial nephritis and uveitis syndrome in a mother and her son. Pediatr Nephrol 2008;23:2091-3.  Back to cited text no. 16
Mandeville JT, Levinson RD, Holland GN. The tubulointerstitial nephritis and uveitis syndrome. Surv Ophthalmol 2001;46:195-208.  Back to cited text no. 17
Taheri S, Taheri D. Short course of cyclophosphamide therapy may reduce recurrence in patients with tubulointerstitial nephritis and uveitis syndrome. Saudi J Kidney Dis Transpl 2009;20:655-7.  Back to cited text no. 18
[PUBMED]  [Full text]  

Correspondence Address:
Ali Derakhshan
Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.335470

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