Uveitis and Renal Dysfunction in a 16-year-old Boy.

A previously healthy 16-year-old boy presents to the emergency department (ED) with a chief complaint of 2 weeks of progressive unilateral eye pain, redness, blurred vision, and photophobia. The presenting ocular complaints have occurred in the context of several months of significantly decreased appetite, early satiety, right-sided lower back pain, and subjective, unintentional weight loss. Back pain is worse after prolonged standing. He has been taking 400 mg of ibuprofen twice weekly for back pain during the 2 weeks before ED presentation. Although he is unable to quantify the degree of weight loss, his mother states that she has had to replace his entire wardrobe with smaller clothes. He denies fevers, rashes, joint pain, night sweats, shortness of breath, cough, vomiting, hematemesis, diarrhea, or hematochezia. He denies a history of sexual activity, substance use, or symptoms of anxiety or depression.Vital signs on presentation are notable for a minimally elevated blood pressure of 122/76 (92nd percentile/90th percentile for height). He is overweight, with a BMI of 27.84 (94.82% for age). No other points are available in our system for comparison. Physical examination is notable for a well-appearing, overweight male in no acute distress. He has significant photophobia with right-sided conjunctival injection and iris nodules. Cardiovascular and pulmonary examination findings are normal. He has no abdominal or costovertebral angle tenderness. He has full range of motion of his spine without pain at the time of examination. Musculoskeletal examination is normal without joint swelling or tenderness. Neurologic examination is symmetrical throughout with 2+ reflexes, normal muscle strength, and normal muscle tone. Gait is normal.Initial laboratory studies are notable for a mildly elevated erythrocyte sedimentation rate of 34 mm/hr (reference range, <20 mm/hr), a mildly elevated alanine aminotransferase level of 49 U/L (0.82 μkat/L) (reference range, 11–30 U/L [0.18–0.50 μkat/L]), and an elevated creatinine level of 1.4 mg/dL (123.8 μmol/L) (reference range, 0.4–1.0 mg/dL [35.4–88.4 μmol/L]). The remainder of the comprehensive metabolic panel, complete blood cell count with differential count, and C-reactive protein level are all normal. Urinalysis is notable for only trace proteinuria. A chest radiograph is negative for any acute cardiopulmonary abnormalities or hilar lymphadenopathy. Sacroiliac joint radiographs are negative for signs of arthritis or ankylosing spondylitis.While in the emergency department, the ophthalmology team is consulted and diagnoses the patient as having acute nongranulomatous uveitis. Per their recommendations, he is started on atropine and prednisolone eye drops for treatment of uveitis. Given his systemic symptoms, he is admitted to the general pediatrics service for evaluation of an underlying systemic process causing anterior uveitis.Inflammatory bowel disease is initially high on the differential diagnosis given the patient’s decreased appetite, reported weight loss, and uveitis. Evaluation shows a normal fecal calprotectin level as well as normal esophagogastroduodenoscopy and colonoscopy. Evaluation for sexually transmitted infections, including chlamydia, gonorrhea, and syphilis, is negative. Testing for other infectious etiologies, such as Mycobacterium tuberculosis, Toxoplasma gondii, Bartonella henselae, Epstein-Barr virus, and herpes simplex viruses 1 and 2 (via DNA polymerase chain reaction from an affected eye), is also negative. Antinuclear antibody titer is positive at 1:320 (reference range, <1:80). Rheumatologic evaluation findings, including levels of complement, antineutrophil cytoplasmic antibody, human leukocyte antigen (HLA-B27), rheumatoid factor, angiotensin-converting enzyme, and lysozyme, are all normal or negative.In the setting of acute nongranulomatous uveitis, urine β2-microglobulin is sent per ophthalmology consultation recommendation, and the result is noted to be markedly elevated at 11.4 mg/L (reference range, 0–0.3 mg/L) on hospital day 4. This finding, in conjunction with a persistently elevated serum creatinine level of 1.5 mg/dL (132.6 μmol/L), prompts concern for the suspected diagnosis and leads to further nephrologic evaluation. Renal ultrasonography reveals mild enlargement of both kidneys with otherwise normal appearance, and the Doppler is normal. Renal biopsy is consistent with interstitial nephritis with tubular injury (Fig). This confirms the suspected diagnosis.Concomitant renal dysfunction with ocular findings has a broad differential diagnosis that includes a multitude of infectious and inflammatory etiologies. Our patient was initially evaluated for inflammatory bowel disease because ulcerative colitis and Crohn disease are known to periodically have ocular and renal manifestations, including uveitis and interstitial nephritis. (1)(2) Results of evaluation for infectious etiologies associated with anterior uveitis, including Epstein-Barr virus–associated mononucleosis, toxoplasmosis, brucellosis, histoplasmosis, and tuberculosis, were normal. Rheumatologic considerations include diseases such as systemic sarcoidosis, systemic lupus erythematosus, Sjogren syndrome, granulomatous polyangiitis, and Behçet disease, although these conditions usually have additional organ system involvement (ie, pulmonary, mucocutaneous findings) not noted in our patient. (3) Our patient did have a positive antinuclear antibody, but this nonspecific finding can be seen in a variety of autoimmune and infectious diseases, and may also be drug-induced. (4) HLA-B27–associated uveitis was also on the differential diagnosis, but our patient tested negative for this antigen.Interstitial nephritis and uveitis can also be related to antecedent medication use; thus, a thorough review of medications used is important in any patient presenting with these findings. A variety of drugs, such as antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), and proton pump inhibitors, have been associated with interstitial nephritis, and medications associated with uveitis include fluoroquinolones, sulfonamides, and tumor necrosis factor α antagonists. (5)(6)(7)Ultimately, our patient’s persistently elevated creatinine concentration, along with uveitis and elevated urine β2-microglobulin level, prompted concern for a rare oculo-inflammatory syndrome called tubulointerstitial nephritis and uveitis (TINU) syndrome. Renal biopsy findings consistent with TINU syndrome confirmed the diagnosis.TINU syndrome is a rare inflammatory syndrome characterized by the presence of both anterior uveitis and interstitial nephritis. It was first described in 1975 by Dobrin et al, (8) and its recognition has steadily increased during the past few decades. TINU syndrome is considered a rare cause of uveitis, thought to be responsible for less than 2% of cases in the general population and approximately 1% of all pediatric uveitis cases. (9)(10) A 2001 review notes that TINU syndrome most often occurs in female patients without any racial or geographical preponderance. (11) In addition, approximately 75% of patients with TINU present with bilateral ocular findings. (3) The median age at onset is earlier in male patients (14 years) compared with female patients (17 years). (3) The typical onset during mid-to-late adolescence highlights the need for pediatricians to recognize TINU syndrome as a disease entity.Although the pathogenesis of TINU syndrome is thought to be a combination of genetic, immunologic, and infectious factors, studies have yet to identify a specific mechanism that accounts for both uveal and renal involvement. It is thought that humoral immunity may play a role, as autoreactive antibodies against renal and ocular antigens have been identified in a very small subset of patients with TINU syndrome. (12)(13) In some patients, a concomitant infection such as chlamydia or Epstein-Barr virus has been implicated in the pathogenesis of TINU syndrome. (14)(15)(16) Our patient’s evaluation did not show evidence of current chlamydial or active Epstein-Barr virus infection. Antecedent drug use, most frequently NSAIDs and antibiotics (particularly β-lactams), within 20 days preceding identification of renal dysfunction has been implicated in several cases. (3)(17) Given the paucity of evidence available regarding antecedent NSAID quantity in patients with TINU syndrome and interstitial nephritis in general, it is unclear whether our patient’s ibuprofen use before presentation may have played a role in his disease process.A diagnosis of TINU syndrome can be established in a patient with both uveitis and clear histologic evidence of interstitial nephritis on renal biopsy. (18) Additional laboratory findings, such as abnormal urinalysis findings (low-grade proteinuria, pyuria, hematuria, white blood cell casts), elevated creatinine concentration, or elevated urine β2-microglobulin level, can support a probable diagnosis of TINU syndrome if accompanied by uveitis. (3)(19) Urine β2-microglobulin is a low-molecular-weight protein filtered through the glomeruli and resorbed by the renal tubules in a healthy kidney. It is excreted into the urine if the renal tubules are damaged and may be elevated even in the absence of proteinuria. (20) When an elevated urine β2-microglobulin level is paired with an elevated serum creatinine level, it has a high positive predictive value in the diagnosis of TINU syndrome among pediatric and young adult patients with uveitis. (20) Systemic sarcoidosis with ocular and renal manifestations can be particularly difficult to distinguish from TINU syndrome. However, sarcoidosis most commonly has pulmonary and mucocutaneous involvement, less commonly has renal involvement, and tends to present later in the fourth or fifth decade of life. (21)(22)(23) In addition, while TINU syndrome is typically associated with anterior, nongranulomatous uveitis, uveitis in sarcoidosis more often has a granulomatous pattern. (19)(24) Furthermore, noncaseating granulomas are the hallmark renal finding in patients with systemic sarcoidosis, whereas nongranulomatous nephritis is the more common finding in TINU syndrome. (3)(19)(21) Uveitis may also be accompanied by an elevated urine β2-microglobulin level in sarcoidosis, emphasizing the utility of renal biopsy as potentially helpful in differentiating the 2 entities. (19)(25)Uveitis associated with TINU syndrome generally responds well to first-line management, typically a course of topical corticosteroid eye drops with or without topical cycloplegic agents such as atropine. (3) Corticosteroid eye drops provide an anti-inflammatory effect, and cycloplegic agents are used to relieve pain related to pupillary contraction. An oral corticosteroid taper is usually prescribed for those with renal impairment due to interstitial nephritis. (18) For those who do not respond to monotherapy with corticosteroids, a second-line immunosuppressant medication may be required. Mycophenolate mofetil has been demonstrated to be effective in patients with acute interstitial nephritis, which is thought to have similar pathophysiology as TINU syndrome. (26) It has also been shown to be an effective monotherapy in pediatric patients with recurrent autoimmune uveitis and is, therefore, an appropriate second-line therapy in patients with TINU syndrome. (26)(27)The prognosis for TINU syndrome is overall positive, with most individuals responding well to systemic corticosteroids. (28) Although uveitis seen in TINU syndrome can relapse, tubulointerstitial nephritis has a much lower risk of recurrence. (28) Most uveitis recurrences occur within the first few months of discontinuing systemic therapy, highlighting the importance of serial follow-up ophthalmologic examinations. (3) Case reports of TINU syndrome in patients with concomitant autoimmune conditions such as rheumatoid arthritis, hypoparathyroidism, and thyroid disease have been documented in adult patients. (17)(29)(30) It is not yet known whether TINU syndrome in children and adolescents may be associated with the development of other such autoimmune diseases later in life. Renal function typically normalizes within 1 year after diagnosis, but patients with TINU syndrome should still be followed by a nephrologist, as there have been occasional reports of acute interstitial nephritis recurrence or progression to chronic renal failure. (17)Throughout his hospital course, our patient experienced relief from his uveitis-related pain and discomfort with atropine and prednisolone eye drops. Blood pressure normalized shortly after admission and remained below the 90th percentile for age for the remainder of the hospitalization. On diagnosis of TINU syndrome, our patient was started on high-dose oral prednisone for treatment of his renal disease. Intermittent mild back pain noted early on during the admission also resolved after starting oral corticosteroids. Follow-up laboratory studies performed 9 days after hospital discharge showed an improved creatinine level to 1.1 mg/dL (97.2 µmol/L) and resolution of trace proteinuria. Repeated ophthalmologic examination revealed inactivity of uveitis after approximately 2 weeks of the aforementioned therapies. He continued oral prednisone use for 6 weeks, until his creatinine level had normalized. The nephrology team intended to monitor the patient’s renal function on discontinuation of therapy, but he was lost to follow-up despite multiple attempts to contact him.Tubulointerstitial nephritis and uveitis (TINU) syndrome should be considered in all children with uveitis and concomitant renal dysfunction.The prevalence of TINU syndrome is likely underestimated, highlighting the need for clinicians to have a high index of suspicion. (9)In patients presenting with uveitis and symptoms such as weight loss, fatigue, malaise, and abdominal/flank pain, consider evaluation of potential infectious and inflammatory etiologies, including urine β2-microglobulin and serum creatinine to screen for evidence of renal tubular damage.When recognized and treated early, pediatric patients with TINU syndrome generally have favorable outcomes but should have long-term follow-up with a nephrologist and ophthalmologist.