The Tubulointerstitial Nephritis and Uveitis Syndrome

SURVEY OF OPHTHALMOLOGY VOLUME 46 • NUMBER 3 • NOVEMBER–DECEMBER 2001

MAJOR REVIEW

The Tubulointerstitial Nephritis and Uveitis Syndrome John T. H. Mandeville, MD, PhD, Ralph D. Levinson, MD, and Gary N. Holland, MD Ocular Inflammatory Disease Center, Jules Stein Eye Institute, and Department of Ophthalmology, UCLA School of Medicine, Los Angeles, California, USA Abstract. The world’s medical literature on tubulointerstitial nephritis and uveitis (TINU) syndrome was reviewed, and data on 133 patients with TINU syndrome were identified. The median age of onset was 15 years (range 9–74 years) with a 3:1 female-to-male predominance. Common laboratory abnormalities included elevated Westergren erythrocyte sedimentation rates and elevated urinary beta-2-microglobulin levels. Ocular symptoms preceded systemic symptoms in 21% of cases, and followed systemic symptoms by up to 14 months in 65% of cases. Uveitis involved only the anterior segment in 80% of cases. Uveitis was bilateral at presentation in 77% of cases. Patients were treated with systemic corticosteroids in 80% of cases and with immunosuppressive drugs in 9% of cases. Uveitis recurred or followed a chronic course in 56% of patients and persisted for several years in some cases. Ocular complications (including posterior synechiae, cataracts, and elevated intraocular pressure) were reported in 21% of cases. The visual prognosis appears to be good. Persistent renal dysfunction was reported in 11% of cases, including five patients who required renal dialysis. TINU syndrome is a distinct clinical entity that may be under-recognized and may account for some cases of unexplained chronic or recurrent uveitis. It is important for ophthalmologists, nephrologists, and primary care providers to be familiar with this disorder to ensure early diagnosis and appropriate treatment. (Surv Ophthalmol 46:195–208, 2001. © 2001 by Elsevier Science Inc. All rights reserved.) Key words. inflammation • interstitial nephritis • iridocyclitis • iritis • kidney • tubulointerstitial nephritis and uveitis syndrome • uveitis

Uveitis in association with acute interstitial nephritis was first described as a distinct entity by Dobrin and associates in 1975.17 Patients with this disorder, which has become known as tubulointerstitial nephritis and uveitis (TINU) syndrome, comprise a subset of those with acute interstitial nephritis, which is thought to be an immune-mediated process that can be drug-related, infection-related, or idiopathic. Acute interstitial nephritis accounts for approximately 10–15% of individuals with acute renal failure.19,87 It commonly presents with non-specific constitutional symptoms, such as fever and flank tenderness. Laboratory investigations reveal proteinuria, hematuria, sterile pyuria, and elevated serum creatinine in affected patients. A renal biopsy is required

for the definitive diagnosis of acute interstitial nephritis, and it typically reveals inflammatory cells and edema in the renal interstitium. TINU syndrome is probably an under-diagnosed disorder. It may account for some cases of “idiopathic uveitis,” if the associated interstitial nephritis was not clinically evident or had resolved by the time the intraocular inflammation developed. In view of the fact that 50% or more of uveitis cases have no identified cause,54 it is important to consider other associations that may lead to a diagnosis or that may suggest pathophysiologic mechanisms of disease. TINU syndrome is of particular interest because of its putative association with common systemic medications and infections. It is therefore appropriate to review exist195

© 2001 by Elsevier Science Inc. All rights reserved.

0039-6257/01/$–see front matter PII S0039-6257(01)00261-2

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ing literature on TINU syndrome to familiarize the ophthalmological community with this disorder. We have identified 133 reported cases of TINU syndrome in 11 languages within 85 publications through June 2000.1,2,4,5,7–14,16–18,20–31,34–39,41–48,50,52,55,57–76, 78–86,88–99 (Two additional cases have been described in articles33,51 that could not be obtained at the time this review was prepared.) Fourteen of these publications have been in the ophthalmic literature since 1987;2,13,16,24,29,54,59,60,73,75,76,80,88,95 the majority of publications have been in the nephrology literature, many without detailed descriptions of the ophthalmologic features of reported cases. We have reviewed each reported case of TINU syndrome and have identified unifying features, such as clinical characteristics, laboratory values, and responses to treatment, to characterize the syndrome more clearly. In addition, we propose diagnostic criteria and possible pathogenic mechanisms for the disease and suggest avenues for further research.

I. Patient Characteristics

MANDEVILLE ET AL

an early ascertainment bias favoring female patients, as the initial reports of TINU syndrome predominantly described women. Thus, the true sex ratio, or whether it is changing, is unknown.

2. Age The median age of onset has been 15 years, ranging from 9 to 74 years of age (Table 1). There was a slight tendency for TINU syndrome to occur earlier in male patients, with a median age of onset of 14 years (mean 16.8 years, range 9–52 years), versus a median age of onset of 17 years in female patients (mean 28.0 years, range 10–74 years). The median age of onset reported prior to 1990 was 20 years (mean 29.1 years, range 10–74 years), and the median age of onset reported since 1990 was 15 years (mean 22.6 years, range 9–68 years). However, this difference may not reflect a true change in the disease, either because of reporting biases soon after the initial reports of the disease, or because of earlier recognition of TINU syndrome after clinicians became more aware of the disease.

A. DEMOGRAPHICS

1. Sex

3. HLA Types

There has been a female predominance in reported cases of TINU syndrome, with a 3:1 femaleto-male ratio (Table 1). There has been an increasing number of reports of male patients with TINU syndrome in the more recent literature; however, whereas male patients constituted only 18% of patients reported prior to 1990, they comprised 34% of patients reported since 1990. There may have been

Several studies have reported the human leukocyte antigen (HLA) specificities of patients with TINU syndrome, as shown in Table 2. The most commonly reported HLA specificities have been HLA-A2 and HLA-A24 (a serologically defined subgroup of HLA-A9).7,20,21,23,25,31,34,36,46,50,57,71,78,85,90,92 In particular, HLA-A24 (or -A9) was identified in 75% of Japanese patients. Both specificities are common in Asian patients, however, and thus they may not be related to the disease. (HLA-A24 is present in 9.5– 61.0% of Asian patients.53) There also may be an association between TINU syndrome and HLA-DR4; not only was it identified in many patients by serologic testing,21,23,36,57,85 but it also can be linked with some of the types reported for other patients (personal communication, Min-Sik Park, DVM, Department of Pathology and Laboratory Medicine, UCLA School of Medicine). The number of reported cases is insufficient for a statistical analysis to assess the relative risks associated with reported HLA specificities. Further study of this issue is warranted. BenEzra6 reported that three of four individuals who developed renal disease and bilateral anterior uveitis after suspected Klebsiella sp. infections were HLA-B27-positive. HLA-B27 is present in as many as 8% of Caucasian individuals, and it is possible that its presence was a chance occurrence. (As no further details were supplied about the patients, they were not included in our list of cases.)

TABLE 1

Demographic Factors and Categorization of Ocular Disease for Reported Patients with TINU Syndrome Age (n  133)a Median Range Sex (n  133)a Female Male Category of uveitis (n  122)a Anterior without other reported sites Posterior or pan uveitis Laterality of uveitis (n  109)a Bilateral Unilateral Alternating a

15 years 9–74 years 98 (74%) 35 (26%) 97 (80%) 25 (20%) 84 (77%) 16 (15%) 9 (8%)

Number of patients for which the factor was identified in published reports.

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TUBULOINTERSTITIAL NEPHRITIS AND UVEITIS SYNDROME TABLE 2

HLA Typing of Reported Patients with TINU Syndrome HLA Specificitiesa A 2 2 11,28 2,32 30 24,28 2,36 24,26 24,33 24,31 24,31 2,24 24,w33 9,33 1,2 9,31 — 2,23 2,11 24(9),26(10) 26(10),11 2,24(9) 2,11 2 2

B

C

39,61 57,35 14,63 8,44 13,35 w22,40 62 35,w62 44 w54,55 w48,7 w48,7 w52,60 65 16 w54,61 — 38,44 54(22),35 70,51(5) w61(40),46 55(22),62(15) w62(15),w46 5,w15 7

w2 w4 w7 w7,4 w4 w3 w3 w3 w3 w1,3 w7 w7 w3 w8 — 1,3 — — w1,3 w7 w3 w1,7 w4 — w3

DR — 6,w52 3,6,w52 3,6,w52 4,7 4,w6 — w12 — 4,w6 4,w12 w8 w8 — 14 4,6,Dw52,53 7 6,7 4,11(5) 4,2 — 12(5) — — —

DQ

Race

Reference

— w1 w1 w1 w53 — — — — — — — — — — 1 w2,w3 — — — — — — — —

White White White White White White White Asian Asian Asian Asian Asian Asian White White Asian White Hispanic Asian Asian Asian Asian Asian White White

7 21 21 21 21 23 25 31 34 36 36 36 36 46 50 57 65 78 85 85 85 85 85 90 92

HLA  human leukocyte antigen. Rodriquez-Perez71 reported predominance of HLA A2, DR1, DR3 in five patients, but did not include individual details and, thus, is not included in this table. a All specificities are listed as originally reported in each reference.

4. Clustering TINU syndrome does not appear to be associated with any racial or ethnic group, with cases reported among Whites, Asians, Hispanics, and Blacks. Race is not specifically mentioned in most reports, however. Gianviti and associates23 reported a case of monozygotic twins who developed acute interstitial nephritis one year apart; only one twin developed uveitis during approximately 3 years of follow-up. There have been no reports of multiple family members with TINU syndrome and no reports of geographic clustering of TINU syndrome cases. This fact argues against either environment or genetic factors as dominant influences in the pathogenesis of the disease. B. RISK FACTORS AND PATHOGENESIS

Acute interstitial nephritis has been associated with a wide variety of drugs (primarily anti-infectives) and infectious agents, as well as with toxins and autoimmune diseases.19 In some patients with acute interstitial nephritis, no precipitating factor can be identified. It is unclear whether patients having infection- or drug-induced renal disease are at

the same risk for uveitis as patients with idiopathic renal disease. The majority of acute interstitial nephritis cases are now attributed to drug-related causes, but because of the extensive use of antibiotics and nonsteroidal anti-inflammatory drugs in patients with infection, it is difficult to determine whether the renal disease is related to infection or to its treatment.19 Furthermore, many of the symptoms associated with renal insufficiency or failure (such as fever, anorexia, or fatigue) could be mistaken for signs of an infectious disease. Risk factors for acute interstitial nephritis were addressed for 122 of the 133 reported cases of TINU syndrome that we reviewed. Approximately one-half (59 of 122) of the cases had no reported risk factors for acute interstitial nephritis. Antecedent drug use was the most commonly identified risk factor. Antibiotic use was documented for 29 of 122 patients (24%), most often to treat respiratory tract infections (15 cases).1,2,8,9,11–13,20,39, 43,65,66,73 A variety of antibiotics were reported; there was no single agent that appeared to be most commonly used by patients with TINU syndrome. Other presumed sites of infections were gastrointestinal tract,2,62,66,90 kidney,73 bladder,91 and

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gynecologic organs;81 the remainder of patients presumably received antibiotics to treat fevers of unknown origin. Antibiotic use did not always precede the onset of renal or ocular symptoms.75 Prior use of nonsteroidal anti-inflammatory drugs was reported for 22 patients (18%).5,11,12,29,39,41,43,45,60–63,65,73, 80,83,84,88,91,94

Several patients with TINU syndrome were found to have serologic evidence of auto-antibodies, including anti-nuclear antibodies,2,23,24,36,38,42,63–65,79,94,97 rheumatoid factor,12,17,35,72 anti-DNA antibodies,42 anti-cardiolipin antibodies,24 and cytoplasmic antineutrophil cytoplasmic antibodies (cANCA).14,64,81 One patient met criteria for both TINU syndrome and Sjögren syndrome.93 There are also reports of patients with TINU syndrome who had family members suffering from autoimmune diseases, including a father with Vogt–Koyanagi–Harada syndrome99 and a sister with ulcerative colitis.94 Because these associations have rarely been reported, they may be coincidental. Other associations have been reported between TINU syndrome and possible infectious causes. TINU syndrome has been reported in patients with reactivation of herpes zoster,50 Epstein–Barr virus infection,1,24,27,50 systemic toxoplasmosis,28 positive PPD skin tests,59 insect bites,72 and generalized lymphadenopathy,28,73 as well as with systemic diseases such as hyperthyroidism,65 hypoparathyroidism,12 rheumatoid arthritis,12,17,35 and elevated angiotensin converting enzyme, a nonspecific marker for granulomatous disease.68 Systemic eosinophilia was reported in 17% of patients (21 of 122 cases). It is unclear whether these associations are coincidental or causally related to TINU syndrome.

TABLE 3

Presenting Signs and Symptoms Identified for Reported Patients with TINU Syndrome Sign or Symptom Fever Weight loss Fatigue, malaise Eye pain or redness Anorexia Weakness, asthenia Abdominal or flank pain Arthralgias, myalgias Headache Polyuria, nocturia Generalized lymphadenopathy Facial edema Sore throat Rash

Number of Patients (n  129) 68 (53%) 60 (47%) 57 (44%) 41 (32%) 36 (28%) 36 (28%) 36 (28%) 22 (17%) 13 (10%) 10 (8%) 1 (1%) 1 (1%) 1 (1%) 1 (1%)

MANDEVILLE ET AL

C. CLINICAL FEATURES

1. Systemic Features Patients with TINU syndrome can present with a variety of non-specific signs and symptoms related to the renal disease, as listed in Table 3. Symptoms were reported for 129 cases. The most common initial symptoms were fever (53%), weight loss (47%), and fatigue and malaise (44%). Other common initial symptoms were anorexia (28%), weakness or asthenia (28%), abdominal or flank pain (28%), and arthralgias or myalgias (17%). Only one patient was reported to have a rash,2 which is part of the rare but classic triad of drug-induced acute interstitial nephritis: rash, fever, and renal insufficiency.15 2. Ocular Features Clinical features of the ocular disease in patients with TINU syndrome are less well-defined than the renal features, with relatively few cases having been detailed in the ophthalmologic literature. Table 4 lists the reported ocular symptoms, findings, and complications. Ocular symptoms were detailed in 71 cases. The most common ocular complaints were eye pain and redness (77%), decreased vision (20%), and photophobia (14%). The category of uveitis could be determined from the clinical descriptions of 122 cases; of these cases, 97 (80%) were described as being an anterior uveitis (Table 1). Anterior segment findings included anterior chamber cells and flare, conjunctival injection, and keratic precipitates (Table 4). In two cases, the keratic precipitates were described as having a granulomatous appearance,24,29 and one of these patients was also noted to have iris Busacca nodules.29 Of the 25 cases described as a posterior or panuveitis, specific posterior findings were detailed in only 17 cases, 10 of which had vitreous inflammatory reactions (Table 4). Retinal vascular lesions comprised the next most prevalent group of posterior findings,2,13,52,57,58,73 including retinal vascular sheathing (two patients), intraretinal hemorrhages and exudates (three patients), arteriovenous crossing changes (two patients), and dilated retinal vessels (two patients). Also reported were cases of focal chorioretinitis (two patients)2,36 and multifocal choroiditis (one patient).16 Pars plana exudates and cells in the anterior vitreous body, features of an intermediate uveitis, were described for five patients.13,67,73 Anterior vitreous humor cells may have been the result of “spill-over” from an anterior uveitis.67,73 No specific descriptions of classic “snowbanks” or “snowballs” (inflammatory condensates in the vitreous humor) were reported. Of note, two of these patients also had retinal find-

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TUBULOINTERSTITIAL NEPHRITIS AND UVEITIS SYNDROME TABLE 4

Characteristics of Uveitis in Reported Patients with TINU Syndrome Characteristic Presenting ocular symptoms (n  71)a Eye pain, redness Blurred vision Photophobia No symptoms Tearing Photopsias Transient visual obscurations Foreign body sensation Floaters Itching Anterior Findings (n  97)a Anterior chamber cell and flare Conjunctival injection Keratic precipitates Nongranulomatous Granulomatous Dry eyes Anisocoria Palpebral conjunctival follicles Eyelid edema Episcleritis Busaca nodules Fibrin in anterior chamber Superficial keratitis Posterior Findings (n  17)a Vitreous humor cells Chorioretinitis Intraretinal hemorrhages Retinal vascular sheathing Cotton-wool spots Dilated retinal vessels Arterio-venous nicking Retinal edema Inactive chorioretinal scar Retinal exudates Intermediate Findings (n  5)a Pars plana exudates or cells in anterior vitreous body Snowbanks or snowballs Ocular Complications (n  28)a Posterior synechiae Optic disc swelling Cataract Elevated intraocular pressure Chorioretinal scarring Cystoid macular edema Rhegmatogenous retinal detachment Macular pucker Neovascularization of the optic disc, transient Permanent, severe visual loss a

Number of Patients (%) 55 (77%) 14 (20%) 10 (14%) 2 (3%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 97 (100%) 66 (68%) 13 (13%) 11 (11%) 2 (2%) 3 (3%) 2 (2%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 10 (49%) 3 (18%) 2 (12%) 2 (12%) 2 (12%) 2 (12%) 2 (12%) 2 (12%) 1 (6%) 1 (6%) 5 (100%) 0 19 (68%) 7 (25%) 6 (21%) 6 (21%) 3 (11%) 2 (7%) 1 (4%) 1 (4%) 1 (4%) 0

Number of patients for which the factor was identified in published reports.

ings, including sheathing of the retinal vessels73 and retinal exudates.13 The ocular disease was initially bilateral or eventually became bilateral in 84 (77%) of 109 cases for which information was available (Table 1). Anterior uveitis was specifically described as being bilateral at the time of initial ocular symptoms in 63 cases (58%). The uveitis was initially unilateral in 25 patients (23%), and nine of those patients later experienced uveitis of the other eye.

II. Course of Disease A. ONSET OF OCULAR SYMPTOMS

Among 120 cases for which information was available, ocular findings preceded (21%), developed concurrently with (15%), or followed (65%) the onset of interstitial nephritis, with a median onset of ocular symptoms one month after the onset of systemic symptoms, as shown in the Fig. 1. Uveitis was documented up to 2 months before, or up to 14 months after the onset of systemic symptoms. Of the 65% of patients who developed ocular symptoms after the onset of systemic symptoms, the median time to onset of ocular symptoms was 3 months after the onset of systemic symptoms. In some cases, onset of uveitis was accompanied by relapse of renal disease, as manifested by a rise in serum creatinine and urinary protein.11,39,47,60 In general, however, the course of the renal disease appeared to be independent from that of the ocular disease. B. RECURRENCES

Recurrences of uveitis were common, having occurred in 52 of 126 cases (41%). We defined recurrence as the development of ocular symptoms or findings of inflammation after a reported period of disease quiescence, regardless of the duration of that interval or treatment during that interval. Information on the number of recurrences is difficult to interpret because of differential follow-up, but of the 52 patients with recurrent uveitis, 27 (52%) were reported to have a single recurrence, while 17 (33%) had two or more recurrences and 8 (15%) had a prolonged course of uveitis with multiple exacerbations.21,24,39,60,84,93,94 First recurrences were reported up to 2 years after the initial bout of uveitis76 and in 10 cases, the recurrent uveitis was reported to develop within 3 months of tapering systemic corticosteroids.21,27,39,58,65,73,78,84 The mean duration of follow-up for reported cases was 22.6 months, ranging from 2 months to 114 months (median 17 months). Of patients with at least 2 years of follow-up, 54% (27 of 50 cases) had recurrent uveitis, compared to 40% (13 of 33 cases) of patients with 12–23 months follow-up and 30% (10

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MANDEVILLE ET AL

Fig. 1. The onset of uveitis relative to symptoms of interstitial nephritis reported for 120 patients with tubulointerstitial nephritis and uveitis syndrome. Uveitis has been reported to precede the nephritis by up to 2 months, and has been reported to follow the nephritis by up to 14 months.

of 33 cases) of patients with less than 1 year of followup. These recurrence rates imply that longer followup will identify more cases of recurrent uveitis. Younger patients (less than 20 years of age) were more likely to have a chronic course of uveitis (persistent inflammation lasting greater than 3 months) than older patients (23% versus 4%, respectively), whereas younger patients were less likely to have recurrences of uveitis than older patients (35% versus 49%, respectively). The duration of follow-up was approximately the same for both groups (median 18 months for the younger group versus 16 months for the older group). C. COMPLICATIONS

Intraocular complications of TINU syndrome were reported in 28 (21%) of 133 patients (Table 4). The formation of posterior synechiae was the most commonly reported complication, found in 68% of cases with complications.13,16,24,27,52,57–59,73,76,80,84,88,91,95 Seven patients were described as having swelling of the optic disk, with or without hemorrhages.16,52,59,80, 88,91,95 Other ocular complications included cystoid macular edema,73,74 macular pucker,26 and chorioretinal scar formation.2,16,73 One case of a rhegmatogenous retinal detachment was also reported.2 Some of the complications found in patients with TINU syndrome could be related to treatment with systemic corticosteroids. Elevated intraocular pressure was reported in six patients,16,24,73,76 one of whom underwent bilateral trabeculectomies that resulted in normalization of the pressure and no loss of visual acuity.16 Authors generally reported that elevations of intraocular pressure were corticosteroidinduced, although it is not clear how this fact was verified. Cataract formation, reported in six patients, was most likely caused by systemic corticosteroid

therapy.20,24,39,99 Furthermore, one case of iatrogenic Cushing syndrome was reported.24 D. OUTCOMES

Very little data were available on visual outcomes, but the risk of vision loss due to TINU syndrome appears to be low. Of importance, there were no cases of permanent, severe vision loss in reported cases of TINU syndrome. Although visual acuity data were available for only 28 eyes, initial visual acuities were rarely worse than 20/40. The worst initial visual acuity was reported by Manjon and associates,52 who described a patient with visual acuities of 20/25 in the right eye, and 20/200 in the left eye; vision returned to “baseline” after 6 months, by the investigators’ report, although a visual acuity measurement was not given. Vision improved to a final acuity of 20/25 or better in both eyes of all patients for whom information was available, with one exception; one eye had a last-reported visual acuity of 20/30, measured 10 days after initiation of therapy.76 In general, renal disease tended to resolve either spontaneously or with corticosteroid therapy. Few cases had recurrence of acute interstitial nephritis or developed chronic renal disease, although some patients were noted to have laboratory evidence of mild renal insufficiency after resolution of their systemic symptoms. Few renal complications of TINU syndrome have been reported, and only five patients were documented to require renal dialysis,11,18,22,48,91 two of whom required chronic dialysis.11,22

III. Pathology Although a reliable diagnosis of tubulointerstitial nephritis can be made from clinical and laboratory

TUBULOINTERSTITIAL NEPHRITIS AND UVEITIS SYNDROME

findings,7,11,13,65,73,80,94,99 renal biopsy is required for the definitive diagnosis of tubulointerstitial nephritis, which must be distinguished from other causes of acute renal failure. All 118 patients with TINU syndrome who underwent renal biopsies had findings consistent with tubulointerstitial nephritis, which is characterized by interstitial edema and infiltration by inflammatory cells. The glomerular and vascular structures are relatively unaffected. The inflammatory infiltrate in kidneys affected by TINU syndrome is composed primarily of mononuclear cells, including lymphocytes, plasma cells, and histiocytes. The majority of lymphocytes were found to be T-lymphocytes expressing IL-2 receptors, indicating an activated state.98 Eosinophils were reported to be present in 40 (34%) and neutrophils were reported to be present in 29 (25%) of the 118 biopsies. Immunofluorescence studies of kidney biopsy specimens failed to show the presence of immunoglobulin or complement components in 66 of 77 reported cases. In the remaining cases, there was immunoglobulin staining of renal tubules,4,9,44,58 glomeruli,71 or mesangium in some cases,35 and the presence of complement components in others.4,45,74,76 Non-caseating granulomata were found in 15 (13%) of the biopsy specimens,1,2,17,18,22,25,35,41,45,61,63,64, 72,79 and six patients were reported to have granulomata on examination of bone marrow aspirates.1,17,25, 35,64 Both lymph node and bone marrow granulomata were reported by Dobrin and associates17 and Iida and associates.35 In addition, three patients had hepatic granulomata.21,72,79 No granulomata were found to contain fungi or acid-fast bacilli on histological examination. There have been no reports describing use of polymerase chain reaction techniques to search for infectious agents. No biopsies of ocular tissues have been reported.

IV. Differential Diagnosis A number of diseases can cause both renal disease and uveitis, including sarcoidosis, Sjögren syndrome, syphilis, systemic lupus erythematosis, Wegener granulomatosis, Behçet disease, Epstein–Barr virus-associated infectious mononucleosis, tuberculosis, toxoplasmosis, brucellosis, and histoplasmosis. The majority of disorders listed here do not result in anterior uveitis alone, which is the most common ocular manifestation of TINU syndrome. Of these disorders, many have typical ocular findings or characteristics that have not been reported for TINU syndrome. For example, ocular toxoplasmosis and ocular tuberculosis are characterized by focal retinal or uveal lesions, respectively, and systemic lupus erythematosis usually results in a scleritis or retinal vasculopathy. Behçet disease presents with paroxysms of severe anterior

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uveitis or with an occlusive retinal vasculitis and is associated with mucocutaneous ulcers. Wegener granulomatosis and infectious mononucleosis do not typically cause chronic anterior or intermediate uveitis. Sarcoidosis and Sjögren syndrome are more likely to cause both ocular and renal symptoms that can be confused with TINU syndrome. A. SARCOIDOSIS

Patients with sarcoidosis are typically found to have elevated immunoglobulin levels and noncaseating granulomata, both of which are frequent findings in patients with TINU syndrome. Angiotensin-converting enzyme, a nonspecific marker for granulomatous disease, is usually elevated in sarcoidosis and was found in one black patient with TINU syndrome.68 Although the uveitis associated with sarcoidosis is usually granulomatous, uveitis associated with TINU syndrome has been described as nongranulomatous with the exception of two cases.24,29 In terms of organs involved, sarcoidosis rarely causes interstitial nephritis and frequently affects the lungs, whereas lung involvement has not been reported in patients with TINU syndrome. In terms of epidemiology, African-Americans have an increased rate of sarcoidosis, whereas only three cases of TINU syndrome have been reported in black patients.27,63,68 Sarcoidosis typically presents during the third to fourth decade of life, whereas TINU syndrome typically presents in the second decade. The two diseases do have overlapping characteristics, however, and TINU syndrome remains a diagnosis of exclusion. B. SJÖGREN SYNDROME

Sjögren syndrome often presents with a lymphocytic interstitial nephritis and occurs predominantly in female patients. Some of the auto-antibodies that are found in Sjögren syndrome have also been reported in patients with TINU syndrome, including anti-nuclear antibodies,2,23,24,36,38,42,63–65,79,94,97 rheumatoid factor,12,17,35,72 and anti-DNA antibodies.42 Like sarcoidosis, Sjögren syndrome typically presents during the third to fourth decade of life. Patients with Sjögren syndrome frequently complain of eye pain and redness, but these symptoms are typically secondary to dry eye rather than to uveitis; dry eye was rarely reported in patients with TINU syndrome (Table 4). C. OTHER

Most investigators ruled out other possible diseases as causes of renal and ocular disease in the cases reported in this review. Nevertheless, Yoshioka and associates98 reported a patient that met diagnostic criteria for Sjögren syndrome, and Guignard and

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Torrado28 reported a case of TINU syndrome in a patient with generalized lymphadenopathy and serologic studies suggestive of active Toxoplasma gondii infection (including complement-fixation test, immunofluorescent antibody, and specific IgM antibodies against T. gondii). No retinal lesions typical of ocular toxoplasmosis were found, however, making a diagnosis of ocular toxoplasmosis unlikely.32 While some patients were reported to have antinuclear antibodies and cANCA, they did not meet diagnostic criteria for specific vasculitides, such as Wegener granulomatosis.

V. Laboratory Investigations A variety of abnormal laboratory values have been reported for patients with TINU syndrome. For illustrative purposes, we have calculated mean values for selected tests, using patient results from multiple publications if laboratory values were reported using the same units. We recognize, however, that methodology and normal ranges may vary among laboratories. Typical normal ranges, based on multiple reports, are listed for purposes of general comparison. Initial laboratory testing in patients with TINU syndrome typically revealed poor renal function, including elevated blood urea nitrogen (BUN) and serum creatinine levels, which often continued to rise during the course of hospitalization. Approximately 90% of patients (96 of 107 cases) had elevated initial serum creatinine, defined as values greater than 1.2 mg/dl, and 64% of patients (68 of 107 cases) had values greater than 2.0 mg/dl (mean 3.62 mg/dl, median 2.3 mg/dl, range 0.5–31.0 mg/dl). Creatinine clearance levels were below 70 ml/min/1.73 m2 in 52 (88%) of 59 patients (median 41 ml/min/1.73m2, range 5.0–87.3 ml/min/1.73m2), indicating impaired renal function. Renal function typically returned to normal or near-normal values upon recovery. Urinalyses were characterized by low-grade proteinuria in 95 (86%) of 110 patients; typically, patients had either 1 or 2 protein on a semi-quantitative 1–4 scale or measurements from 250–1000 mg/ 24 hr. Microscopic hematuria was found in 42% of cases, and urinary leukocytes were identified in 55% of cases. Only 3% of cases were reported to have urinary eosinophils, which is a nonspecific finding, but is one that might be helpful in differentiating acute interstitial nephritis from tubular necrosis. In addition, 47% of cases reported normoglycemic glucosuria. Urinary beta-2 microglobulin levels, a marker for interstitial nephritis, were elevated in each of the 34 cases tested, often to markedly high levels. The mean beta-2 microglobulin level was 28.6 mg/dl, ranging from 0.481 to 119.5 mg/dl (typical normal value 0.37 mg/dl). Laboratory investigations also revealed evidence of systemic inflammation. The initial Westergren eryth-

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rocyte sedimentation rate was elevated (50 mm/ hr) in 83 (89%) of 93 patients and markedly elevated (100 mm/hr) in 40 (37%) of 93 patients, with a mean value of 88 mm/hr, median value of 90 mm/ hr, and range of 11–160 mm/hr (typical normal range for patients in this age group 20 mm/hr). The serum IgG levels were also elevated in 58 (83%) of 70 patients tested, with a mean of 2020 mg/dl for all patients tested (patient range, 620–3514 mg/dl; typical normal range, 650–1500 mg/dl). Circulating immune complexes were identified in some patients.26,27,38,39,86 Anemia was a common finding in patients with TINU syndrome, with 86 (96%) of 90 patients reported to have abnormally low hemoglobin concentrations, with a mean initial hemoglobin of 10.4 g/dl for all patients tested (patient range, 5.5–14.0 g/dl; typical normal range 12.2–16.6 g/dl).

VI. Therapy No prospective, randomized studies have addressed the efficacy of treatment for acute interstitial nephritis. It may resolve spontaneously, after discontinuance of an inciting drug or treatment of an underlying infection. Systemic corticosteroids are generally reserved for cases of progressive renal failure. In the cases reported here, there was no clear relationship between age and response to treatment. The anterior uveitis of TINU syndrome has been treated most commonly with topical corticosteroids and cycloplegic agents. Topical corticosteroids alone were used to treat 21 (17%) of 123 patients. Three patients received periocular injections of corticosteroids to treat the uveitis.21,41,76 Systemic corticosteroids were used for 99 patients (80%), 13 (11%) of whom received such treatment exclusively for the ocular disease. Initial attacks of uveitis generally responded well to treatment. Of 126 patients for whom information was available, 56 (44%) had complete resolution of uveitis within 3 months of initial therapy, whereas 18 (14%) had a chronic course of uveitis (lasting 3 months); the remaining 52 patients (41%) had recurrences of uveitis (see section IIB). It is possible that chronic or recurrent cases are more common; the number of cases reported may be limited by the short duration of follow-up in some studies. In 11 cases, immunomodulatory chemotherapeutic agents were used to treat the uveitis.21,24,39,52,65,77,78 These drugs were used either to treat uveitis that was not responding to systemic corticosteroids or out of concern for the ocular or systemic toxicities of corticosteroids. The specific agents used included azathioprine,21,24,39,78 methotrexate,24,65 cyclosporine,24,52,78 and mycophenolate mofetil.77 One patient with panuveitis did not respond to prednisone or azathioprine, then initially responded to cyclosporine, but

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was later treated with mycophenolate mofetil for recurrent uveitis, with control of inflammation.77,78 Gion and associates24 reported one patient who did not respond to methotrexate but was successfully treated with azathioprine and cyclosporine. Although the use of immunosuppressive drugs to treat the refractory uveitis of TINU syndrome is promising, the potential renal and hepatic toxicity of these drugs is a concern in patients who may already have active renal or hepatic inflammation or both.21, 44,72,79 At the time of this review, there had been no reports of serious toxic effects from use of immunosuppressive drugs for treatment of TINU syndrome. A limited course of topical corticosteroids alone was effective for treating recurrent uveitis in 26 (50%) of 52 cases for which specific data was available; one case required chronic topical therapy.17 The other recurrences were treated with systemic corticosteroids or immunosuppressive drugs. In the absence of larger, controlled studies, however, it is difficult to assess the efficacy of treatment for this uncommon disease.49

VII. Discussion A. DILEMMAS IN EVALUATION AND DIAGNOSIS

In evaluating patients with TINU syndrome, a search must be made for diseases that are known to cause both acute interstitial nephritis and uveitis, such as sarcoidosis and Sjögren syndrome. The initial description of TINU syndrome by Dobrin and associates17 included granulomata and eosinophils in the kidney and bone marrow, which are not found in the majority of cases in the literature. It is unknown whether acute interstitial nephritis from any cause is capable of generating uveitis, but the cases reviewed herein have had probably drug-induced, post-infectious, and autoimmune causes. It is therefore likely that TINU syndrome can be associated with any cause of acute interstitial nephritis. Hirano and associates31 reported the use of a Gallium citrate scan that showed inflammation in the eyes and kidneys prior to the onset of clinical uveitis. The fact that such sub-clinical inflammation of the eye could be found in an acute interstitial nephritis patient who later developed TINU syndrome suggests that there may be a number of individuals who develop ocular and renal inflammation without ever coming to the attention of a clinician. Conversely, it is possible that some uveitis patients without constitutional symptoms could be suffering from sub-clinical tubulointerstitial nephritis. Physicians should suspect the presence of renal disease and order appropriate tests of renal function in patients with uveitis and concurrent or past constitutional symptoms, although test results may have

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normalized if the uveitis has developed long after the onset of systemic symptoms. Because the definitive diagnosis of tubulointerstitial nephritis requires renal biopsy, which is usually performed only in cases of acute renal failure, it is likely that patients with less severe disease will go undiagnosed.15 Hence, the true frequency of TINU syndrome may be under-reported. The urinary beta-2-microglobulin, a marker for interstitial nephritis that was elevated in all patients tested, may be particularly helpful in the diagnosis of TINU syndrome, especially when a renal biopsy is not indicated. The beta-2-microglobulin may remain elevated for months after the routine urinalysis and serum creatinine have returned to normal.85 The prevalence of TINU syndrome has been reported to be as high as 2% in patients from a uveitis specialty clinic,73 although this number has been challenged.6 It is conceivable that some patients with chronic, relapsing idiopathic uveitis may in fact have TINU syndrome. B. POSSIBLE PATHOGENIC MECHANISMS

The pathogenesis of TINU syndrome remains unknown. The association between acute interstitial nephritis and uveitis could either be due to a single primary disease process affecting both the kidney and the eye, or the eye could be secondarily inflamed as a result of immune reactions generated during the renal disease. The fact that uveitis symptoms precede the onset of systemic symptoms in roughly onefifth of cases (see Fig. 1) argues against secondary ocular involvement. It is possible, however, that patients with TINU syndrome who first present with uveitis already have sub-clinical renal impairment and that renal symptoms are not apparent until the onset of renal failure, when they progress rapidly.15 A role for cell-mediated immunity is supported by cytologic studies revealing a preponderance of T-lymphocytes in the renal interstitium.7,20,21,36,63,64,71,82,84,98 These T-lymphocytes appear to be activated, as evidenced by IL-2 receptors on the cell surface.98 Also in support of a disturbance in cell-mediated immunity are lymphokine abnormalities,7,21 a decreased CD4/CD8 ratio,98 soluble IL-2 receptors in the serum,3 anergy,17,21,90 and dramatic response of renal disease to corticosteroids.31 The role of HLA in TINU syndrome remains to be determined. The report of monozygotic twins, one of whom developed acute interstitial nephritis while the other developed TINU syndrome,23 implies that genetics may play a role, although environmental factors may also be important for the development of ocular disease. Johnson and associates40 have reported that mycoplasma-like organisms (MLO), which have been implicated in chronic uveitis in humans, are also capable of causing uveitis in mice. Interestingly, all MLO-

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inoculated mice that developed uveitis (12%) also developed progressive tubulointerstitial nephritis, whereas noninoculated mice did not. MLO-parasitized leukocytes were found in affected kidneys, and several of the affected kidneys were found to have granulomata. Although the role of MLO in human disease is controversial, this type of direct infection of both eye and kidney is one possible pathogenetic mechanism for TINU syndrome, albeit unlikely to explain the majority of cases. Some cases of TINU syndrome may be drug-related. Drugs can induce inflammatory responses in a variety of ways: by hypersensitivity, by direct induction of antibodies, by acting as a hapten, by stimulation of cytokine production, or by causing a vasculitis.56 Alternatively, anti-infective drugs could release antigens from dying organisms, in some cases inducing a Jaresch–Herxheimer-like reaction.56 There is evidence that ibuprofen and sulfonamides, among others, are capable of inducing both a uveitis and interstitial nephritis.15,56 Interestingly, acute interstitial nephritis has been associated with rifampin, while uveitis without nephritis has been associated with rifabutin, the former derived from rifamycin B and the latter from rifamycin S. It is conceivable that structural differences in these molecules could relate to different manifestations of secondary inflammatory disease. The interstitial nephritis associated with rifampin is thought to involve cell-mediated immunity. The uveitis associated with rifabutin resolves with withdrawal of the offending drug, but the uveitis associated with TINU syndrome may last for years. No investigators have reported rechallenging patients with drugs suspected of causing TINU syndrome. Once an inflammatory disease is initiated, it may be sustained by the development of an autoimmune response. Renal tubular and ciliary body epithelia share several functions, including active electrolyte transport sensitive to carbonic anhydrase inhibitors. It is conceivable that they share closely related antigens that could account for cross-reactivity. Specific basement membrane antigens have been found to be immunogenic in animal models of acute interstitial nephritis, and some patients with acute interstitial nephritis have antibodies to tubular basement membranes. Nevertheless, only 2 of 77 patients with TINU syndrome were specifically reported to have immunofluorescent staining of renal tubular basement membranes for antibody deposition.4,58 Based on published reports, TINU syndrome appears to be a disease predominantly of young women. In contrast, the medical literature does not suggest an age or sex predilection for isolated interstitial nephritis. When first described, acute interstitial nephritis was more commonly associated with infectious agents such as Streptococcus sp., Corynebacterium

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diphtheria, cytomegalovirus, or Epstein–Barr virus, agents that are commonly first encountered in childhood. Today, the majority of acute interstitial nephritis cases are attributed to drug exposure, especially antimicrobial agents, which are used by all age groups. The demographics of initially reported cases of TINU syndrome may have reflected a higher rate of acute interstitial nephritis in young individuals several years ago or may reflect early ascertainment bias, based on initial description of the disease. C. DIAGNOSTIC CRITERIA

There are no standard diagnostic criteria for TINU syndrome. Based on information from this review and on knowledge of the manifestations of acute interstitial nephritis, detailed diagnostic criteria for TINU syndrome have been formulated with the assistance of Dr. James T. Rosenbaum, MD, who first described TINU syndrome in the ophthalmic literature (Table 5). Due to the protean nature of disease findings, criteria are based on the likelihood of having TINU syndrome and categorized as “definite,” “probable,” or “possible.” Diagnosis of TINU syndrome is based on the strength of findings that support a diagnosis of acute interstitial nephritis (histopathologic findings or clinical criteria) and the characteristics of the associated uveitis (typical, based on this review, or atypical). As TINU syndrome is a diagnosis of exclusion, diseases known to cause uveitis and interstitial nephritis must be ruled out first. In particular, sarcoidosis should be considered. A definite diagnosis of TINU syndrome requires histological confirmation or extensive clinical evidence of acute interstitial nephritis and the presence of a bilateral anterior uveitis, as evidenced by cell and flare in the anterior chamber on ophthalmologic examination. The inflammation need not affect both eyes concurrently or symmetrically and may include the presence of an intermediate or posterior uveitis, but it must occur within 12 months of the acute interstitial nephritis. Clinical signs and symptoms may include eye pain, redness, photophobia, and blurred vision. While a renal biopsy is required to prove the presence of interstitial nephritis, the individual risks and benefits of the procedure must be weighed for each patient. In the absence of a renal biopsy, most nephrologists consider extensive clinical evidence to be sufficient for diagnosis of acute interstitial nephritis. For diagnosis, the following three clinical criteria must be fulfilled: 1) abnormal renal function; 2) abnormal urinalysis; and 3) history of acute systemic illness that lasted at least 2 weeks, characterized by various signs, symptoms and laboratory findings. See Table 5 for findings that fulfill each of these criteria. If atypical clinical features

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TABLE 5

Diagnostic Criteria for Tubulointerstitial Nephritis and Uveitis Syndrome The diagnosis of TINU syndrome requires the presence of both acute interstitial nephritis (AIN) and uveitis, without other known systemic diseases that can cause either interstitial nephritis or uveitis. Cases are categorized further as “definite,” “probable,” or “possible” on the basis of 1) the diagnostic criteria for AIN as defined below; and 2) the clinical characteristics of uveitis as defined below. Definite TINU syndrome • AIN diagnosed histopathologically or clinically (complete criteria) and typical uveitis Probable TINU syndrome • AIN diagnosed histopathologically and atypical uveitis or • AIN diagnosed clinically (incomplete criteria) and typical uveitis Possible TINU syndrome • AIN diagnosed clinically (incomplete criteria) and atypical uveitis Diagnostic Criteria for Acute Interstitial Nephritis • Histopathologic diagnosis: renal biopsy consistent with tubulointerstitial nephritis • Clinical diagnosis:a the presence of the following criteria (a case is considered to have “complete criteria” if the three factors listed below are present; a case is considered to have “incomplete criteria” if less than three factors listed below are present): 1. Abnormal renal function (elevated serum creatinine or decreased creatinine clearance) 2. Abnormal urinalysis: increased beta-2 microglobulin, low-grade proteinuria (a level below that seen in patients with nephrotic syndrome [2 or less on a semi-quantitative test, or a spot urinary protein/urinary creatinine ratio of 3, or 3.0 gm protein/24 hr in an adult or 3.5gm protein/1.73m2/24hr in a child]), urinary eosinophils, pyuria or hematuria without infection, urinary white cell casts, or normoglycemic glucosuria 3. A systemic illness lasting 2 weeks, characterized by a combination of the following symptoms and laboratory findings: a. Signs and symptoms: fever, weight loss, anorexia, malaise, fatigue, rash, abdominal or flank pain, arthralgias, or myalgias b. Laboratory findings: evidence of anemia, abnormal liver function, eosinophilia, or Westergren erythrocyte sedimentation rate 40 mm/hr Uveitis Characteristics • Typical 1. Bilateral anterior uveitis with or without intermediate uveitis or posterior uveitis 2. Onset of uveitis 2 months before or 12 months after AIN • Atypical 1. Unilateral anterior uveitis or intermediate uveitis or posterior uveitis or a combination of these categories 2. Onset of uveitis 2 months before or 12 months after AIN a If atypical clinical features are present, or if the renal disease does not improve after 6 weeks with appropriate therapy, a renal biopsy is recommended.

are present, or if the renal disease does not improve after 6 weeks with appropriate therapy, a renal biopsy is recommended. A diagnosis of “probable TINU syndrome” is assigned if 1) uveitis is atypical despite histopathologic confirmation of acute interstitial nephritis, or 2) the evidence of acute interstitial nephritis is not strong (lack of histological confirmation and only partial clinical criteria), even if the associated uveitis is typical. Some patients with unilateral uveitis may eventually develop bilateral uveitis and can then be given a diagnosis of definite TINU syndrome. A diagnosis of “possible TINU syndrome” is given to patients who have both evidence of acute interstitial nephritis and the presence of intraocular inflammation, without evidence of other associated systemic disease, if both 1) the evidence of acute interstitial nephritis is not strong and 2) the associated uveitis is atypical.

The clinician must have a high index of suspicion to diagnose TINU syndrome, as the renal disease and uveitis may occur many months apart. The level of suspicion should be raised for young female patients. Any patient with a history of acute interstitial nephritis who has ocular complaints, such as eye pain, blurry vision, or red eye, should be evaluated by an ophthalmologist. For patients presenting initially with uveitis, the constitutional symptoms listed in Table 3 should prompt the ophthalmologist to investigate renal function with a serum creatinine level and routine urinalysis. If the serum creatinine or urinalysis is found to be abnormal, a urinary beta-2-microglobulin level should be considered. Other helpful tests include an erythrocyte sedimentation rate, which may be markedly elevated, and a complete blood count, which may reveal anemia. Once the diagnosis of renal and ocular disease has been made, a kidney biopsy should be considered to confirm the diagnosis of tubulointerstitial

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nephritis, if there are not extensive and typical clinical criteria to establish the diagnosis. The ophthalmologist should also consider TINU syndrome in the evaluation of patients with apparently isolated, undiagnosed recurrent or chronic uveitis. In these cases, the acute interstitial nephritis may have resolved and the renal function returned to normal. A detailed history may reveal evidence of prior renal insufficiency, an undiagnosed systemic illness consistent with transient renal failure, or adverse reactions to medications. These clues may eventually lead to a diagnosis of TINU syndrome.

VIII. Summary In summary, TINU syndrome is a distinct entity that tends to affect young women, although both sexes and older patients may also be affected. The renal disease is characterized by acute interstitial nephritis with a predominantly T-lymphocyte infiltrate, whereas the ocular disease is most often a bilateral anterior uveitis that may occur before, simultaneous with, or after the onset of renal disease. Cell-mediated immune dysfunction has been implicated in the pathogenesis of TINU syndrome, but a cause has not yet been identified. Laboratory findings are notable for markedly elevated erythrocyte sedimentation rate, elevated urinary beta-2-microglobulin, normochromic/normocytic anemia, elevated serum creatinine, and elevated immunoglobulins. The disease has a good prognosis generally, and topical or systemic corticosteroids seem to be beneficial. Although a review of this nature clearly has its limitations, we have gained valuable information regarding the characteristics and outcomes of TINU syndrome. Long-term ophthalmological follow-up is required, due to the high frequency of recurrent and chronic uveitis, and long-term studies are needed to characterize the recurrence rate of uveitis and ophthalmologic complications of TINU syndrome more precisely.

Method of Literature Search Articles cited in this review were identified from a MEDLINE search of the years 1966–1999, using the keywords interstitial nephritis and uveitis and from a review of the reference lists from each article. Two articles identified in this search33,51 were not cited in the review because they were not available through the interlibrary loan services at either the University of California, Los Angeles or the National Library of Medicine. Also included with permission of the authors were two articles16,24 in press at the time of manuscript preparation; they were subsequently published in 2000. Translations were obtained for all non-English articles.

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Outline I. Patient characteristics A. Demographics 1. Gender 2. Age 3. HLA types 4. Clustering B. Risk factors and pathogenesis C. Clinical features 1. Systemic features 2. Ocular features II. Course of disease A. Onset of ocular symptoms B. Recurrences C. Complications D. Outcomes III. Pathology IV. Differential diagnosis V. Laboratory investigations VI. Therapy VII. Discussion A. Dilemmas in evaluation and diagnosis B. Possible pathogenic mechanisms C. Diagnostic criteria VIII. Summary Min-Sik Park, DVM, Immunogenetics Laboratory, Department of Pathology and Laboratory Medicine, UCLA School of Medicine, performed the analysis of HLA types. Minhtri Nguyen, MD, Division of Nephrology, Department of Medicine, UCLA School of Medicine, provided suggestions regarding appropriate criteria for diagnosis of acute interstitial nephritis. James T. Rosenbaum, MD, Departments of Ophthalmology, Medicine, and Cell Biology, Oregon Health Sciences University, participated in the formulation of diagnostic criteria for TINU syndrome. The following individuals translated articles published in non-English language journals: Adil Abduragimon, PhD, Gabriele Dillman, PhD, Yasmin B. Harvey, Takao Hashimoto, MD, PhD, Jana Hatch, Sandy Y. Lee, MD, Bettina S. Prost, JD, Federico Velez, MD, and Mirka Vuollo. Supported in part by Research to Prevent Blindness, Inc. (Dr. Holland), the Skirball Foundation, Los Angeles, CA (Dr. Holland), and the David May II Endowed Professorship (Dr. Holland). Dr. Holland is a recipient of a Research to Prevent Blindness, Inc.—Lew R. Wasserman Merit Award. The authors have no proprietary or commercial interest in any product or idea discussed in this article. Reprint address: Gary N. Holland, MD, Jules Stein Eye Institute, 100 Stein Plaza, UCLA, Los Angeles, CA 90095-7003 USA.