Tubulointerstitial Nephritis and Uveitis
Tubulointerstitial Nephritis and Uveitis Syndrome (TINU) describes a rare form of bilateral anterior uveitis found in patients with acute kidney inflammation. The uveitis is usually mild and the nephritis self-limited. However, cases of chronic uveitis and renal failure have been reported. It was first described in 1975 by Dobrin et.al.
Although the cause of TINU is unknown, research has revealed various associations. Certain HLA genotypes (including HLA-DQA1*01, HLA-DQB1*05, and HLA-DRB1*01) increase the relative risk of developing TINU in certain populations . Medications such as NSAIDS and antibiotics have also been implicated, the drug causing hypersensitivity reaction or hapten-induced cytokine production and immune reaction. Another possibility links dysfunction or targeted disruption of similar enzymes in the renal tubule and ciliary epithelium.
Prevalence: TINU is a relatively rare disease, accounting for less than 1-2% of all patients presenting to ophthalmology . It is also a small percent of patients with a first episode of acute non-granulomatous anterior uveitis . The true prevalence is unknown and probably higher due to undiagnosed cases labeled idiopathic. On average, TINU occurs in approximately 65% of patients with TIN .
Epidemiology: TINU occurs predominately in young females. The median age of onset is 15 years old with patient’s ages ranging from 9 to 74 . It affects both sexes, with an overall predominance of females but a trend towards a male predominance in younger age groups . There is no association with particular racial or ethnic groups, or any geographical regions .
The underlying pathogenesis of TIN and TINU is unknown, but thought to be immune mediated . Renal biopsy of patients with TIN typically shows inflammatory cells (lymphocytes, plasma cells and histiocytes) and edema in the renal interstitium . The glomerulus and blood vessels are relatively spared. Immune precipitates are not found.
Patients will usually present with typical anterior uveitis symptoms (eye pain, redness, decreased vision, and photophobia). Symptoms of TIN are vague and include fever, malaise, fatigue and flank pain. The general malaise usually precedes the ocular findings and needs to be elicited during the initial interview. The ocular symptoms can precede (21%) by up to two months, occur concurrently (15%), or follow TIN (65%) .
About 80% of the cases present as acute onset bilateral non-granulomatous anterior uveitis. However, there have been case reports of intermediate uveitis, posterior uveitis, and panuveitis . Intermediate uveitis has also been reported. Other exam findings may include posterior synechiae, vitreous cells, optic disc swelling, and macular edema.
Patients will usually present with typical anterior uveitis symptoms (eye pain, redness, decreased vision and photophobia).
A reliable diagnosis can usually be made from a full ophthalmic exam and usual laboratory evaluation.
In addition, beta-2 microglobulin detection in the urinalysis and serum (elevated), proteinuria, presence of eosinophils, pyuria or hematuria, urinary white cells casts, and normoglycemic glucosuria may be noted. However, a definitive diagnosis of TIN can only be made with renal biopsy. Pathology will demonstrate eosinophilic and mononuclear cellular infiltrates with glomerular sparing. Blood urea nitrogen and creatinine are elevated in renal compromise.
A number of conditions can present with both renal manifestations and uveitis. These include: TINU, systemic lupus erythematosus, Sjogren's syndrome, syphilis, sarcoidosis, granulomatosis with polyangiitis (formerly Wegener's), Behcet's disease, Epstein-Barr virus associated infectious mononucleosis, tuberculosis, toxoplasmosis, brucellosis, histoplasmosis, and Hyper IgG4 disease .
Standard treatment for anterior uveitis with topical steroids can be effective. However, with the high frequency of recurrent disease, long term follow-up is recommended for these patients . If kidney functions do not quickly normalize, a short course of high dose IV or oral steroids is often used. Coordination by nephrology and ophthalmology can be useful. Steroid sparing immunomodulatory therapy may be needed for severe inflammation.
Long term ocular complications are rare. Uveitis will often persist longer than the nephritis and may require long term local therapy, rarely lasting more than a year . Recurrence of uveitis can occur in patients with TINU, reported as high as 40% . Most recurrences occur within the first few months of stopping therapy, but have occurred as late as two years later . Renal outcomes are also generally good, with nephritis often spontaneously resolving, but there have been cases of chronic renal failure following TINU . In contrast to uveitis, nephritis rarely recurs.
- Amaro D, Carreño E, Steeples LR, Oliveira-Ramos F, Marques-Neves C, Leal I. Tubulointerstitial nephritis and uveitis (TINU) syndrome: a review. Br J Ophthalmol. 2020 Jun;104(6):742-747.
- 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 Sep;59(3):325-33.
- Levinson RD, Park MS, Rikkers SM, Reed EF, Smith JR, Martin TM, Rosenbaum JT, Foster CS, Sherman MD, Holland GN. Strong associations between specific HLA-DQ and HLA-DR alleles and the tubulointerstitial nephritis and uveitis syndrome. Invest Ophthalmol Vis Sci. 2003 Feb;44(2):653-7.
- Mackensen et al Br J Ophth. 2011,95:971-976.
- Mackensen et al Curr Opin Ophth. 2009,20:252-531.
- Birnbaum, et. al. Arch Ophthalmol. 2012;130(11):1389-1394.
- Mandeville JTH, Levinson RD, Holland GN. The Tubulointerstitial Nephritis and Uveitis Syndrome. 2001. Surv Ophthalmol. 46:195-208 .