Tubulointerstitial nephritis and uveitis (TINU syndrome)

INTRODUCTION — A unique subset of patients with interstitial nephritis has the tubulointerstitial nephritis and uveitis (TINU syndrome). First described in 1975 [1], more than 250 cases have now been reported [2,3]. The majority of cases have been documented in the ophthalmology and pediatric nephrology literature via case reports and small descriptive series.

PATHOGENESIS — TINU is thought to be an immune-mediated process, the underlying mechanisms for which are not well understood [4]. Limited data suggest that modified C-reactive protein (mCRP), an autoantigen common to both the uvea and renal tubular cells, may be involved in the pathogenesis [5]. In a study of 97 patients with various kidney diseases and 40 individuals who were healthy, the prevalence of immunoglobulin G (IgG) antibodies directed against mCRP was significantly higher among patients with TINU syndrome (100 percent) compared with patients who had Sjögren-associated interstitial nephritis (29 percent), drug-induced interstitial nephritis (36 percent), glomerulonephritis (5 percent), or those who were healthy [5]. Another study by the same group confirmed that the mCRP is higher among patients with TINU syndrome and late-onset uveitis compared with those with drug-induced interstitial nephritis [3].

The inflammation in TINU syndrome is thought to be T-lymphocyte driven, based upon the histologic findings. In contrast, immune cells in patients with TINU syndrome have a paradoxical suppression of cytokine production and a decrease in peripheral immune response, as demonstrated by anergy to skin testing. 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 [6,7].

RISK FACTORS AND ASSOCIATIONS — No identifiable risk factors have been found in at least 50 percent of cases. In some instances, prior infection or the use of specific drugs (antibiotics to treat upper respiratory infections and nonsteroidal antiinflammatory drugs [NSAIDs]) has been implicated [3,4]. The Chinese herb, "goreisan," has been associated in a case report [8]. Although causality is unclear, concurrent Chlamydia and Epstein-Barr virus infections have been described [9,10]. TINU syndrome has also been reported in patients with autoimmune diseases like hypoparathyroidism [11], thyroid disease [3,12], immunoglobulin G4 (IgG4)-related autoimmune disease [13], rheumatoid arthritis [11,14], and thrombotic microangiopathy [15].

EPIDEMIOLOGY — TINU is a rare syndrome [16,17]. Most patients with TINU are adolescents and young women, with a median age of 15 years [18]. It has also been reported in older adults [19,20]. All series report a female-to-male predominance [3,4], with no particular racial affinity.

Although sporadically reported [21-23], there has been no definitive identified familial, genetic, or geographic clustering. In the past, various human leukocyte antigen (HLA) types have also been ascribed without inter-series consistency. Subsequently, however, a strong association was noted with HLA-DQA1*01, HLA-DQB1*05, and HLA-DRB1*01 in a series of 18 patients [24].

CLINICAL AND LABORATORY MANIFESTATIONS — In addition to uveitis and interstitial nephritis, TINU may be associated with systemic findings including fever, weight loss, fatigue, malaise, anorexia, asthenia, abdominal and flank pain, arthralgias, myalgias, headache, polyuria, and/or nocturia.

Uveitis — Patients with uveitis present with eye pain or redness; it is typically bilateral, although unilateral or alternating uveitis can be observed. This can also be accompanied by photophobia and decreased visual acuity. (See "Uveitis: Etiology, clinical manifestations, and diagnosis".)

Since the uveitis is predominantly anterior, the majority of clinical findings include anterior chamber cells and flare, conjunctival injection, keratic precipitates, and dry eyes [25]. Posterior uveitis can also be seen, resulting in vitreous humor cells, chorioretinitis, intraretinal hemorrhages, retinal vascular sheathing, cotton wool spots, dilated retinal vessels, arteriovenous nicking, and retinal edema [4].

The uveitis has been observed to occur two months before, concurrently, and up to 14 months after the onset of the interstitial nephritis [4]. The majority of cases present after the onset of kidney disease. In a case series cited above, among 31 patients with biopsy-proven TINU syndrome, 18 patients (58 percent) developed uveitis 2 to 11 months after a diagnosis of interstitial nephritis was made by kidney biopsy [3].

In approximately 20 percent of patients with uveitis, intraocular complications have been noted. These include posterior synechiae, optic disc swelling, cystoid macular edema, chorioretinal scar formation, cataracts, and glaucoma.

Kidney manifestations — Kidney manifestations with TINU syndrome are typical for acute interstitial nephritis. These may include flank pain, sterile pyuria, hematuria, proteinuria (usually subnephrotic range), kidney function impairment, and acute kidney injury (AKI) (see "Urinalysis in the diagnosis of kidney disease"). Multiple proximal and distal tubular defects can be commonly seen, resulting in aminoaciduria, glucosuria, phosphaturia, and acidification defects [26-28] (see "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance"). Kidney sonography can demonstrate marked swelling of the kidneys.

Laboratory findings — There are no specific serum markers or laboratory findings that are unique to patients with TINU. Laboratory findings may include leukocyturia, eosinophilia, anemia, slightly abnormal liver function tests, and an elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) [3]. Glycosuria may be observed [3]. Associations of TINU with a variety of serologic markers in the absence of their correspondent disease have been reported. Thus, the disorder has been associated with antineutrophil cytoplasmic antibody (ANCA) [29]; antinuclear antibody (ANA), an autoantibody directed against renal tubular cells [30]; rheumatoid factor (RF); and hypocomplementemia [31]. In addition, antibodies that react to both tubular and uveal cells have been identified in the serum of a patient with TINU syndrome [2].

Elevations have been found in serum levels of beta-2 microglobulin and Krebs Von Den Lunge-6 (KL-6), a glycoprotein found in lung tissue of normal individuals as well as in the distal renal tubules of patients with TINU syndrome [32]. However, in a larger study by the same group, serum and kidney KL-6 levels were not different between patients with TINU syndrome and drug-induced interstitial nephritis [3].

DIAGNOSIS AND HISTOLOGIC FINDINGS — The definitive diagnosis of TINU syndrome is nonspecific and is suggested by the combination of uveitis and kidney involvement, with kidney biopsy consistent with acute interstitial nephritis. On light microscopy, typical biopsy findings include tubulointerstitial edema and infiltration of inflammatory cells composed mainly of mononuclear cells, such as lymphocytes, plasma cells, and histiocytes. Eosinophils and noncaseating granulomas are frequently seen, with neutrophils also being observed [33]. Glomerular and vascular structures are generally preserved. Findings with immunofluorescence and electron microscopy are also nonspecific.

Patients who are determined to have acute interstitial nephritis on kidney biopsy and have no obvious, underlying cause may require a slit lamp examination to exclude uveitis and TINU syndrome. However, many patients with TINU syndrome present with late-onset uveitis, and, thus, the initial slit lamp examination will be negative (see 'Uveitis' above). Such patients who are suspected as having TINU but have a negative slit lamp examination should be followed for at least 12 months for the emergence of signs and symptoms of uveitis.

Bone marrow and lymph node granulomas can be present as well, representing the systemic nature of the disease.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for interstitial nephritis occurring in association with ocular findings is broad. Thus, the following disorders should be considered in this setting:

●Sarcoidosis

●Sjögren's disease

●Systemic lupus erythematosus

●Granulomatosis with polyangiitis

●Behçet syndrome

●Infectious diseases, such as tuberculosis, brucellosis, toxoplasmosis, and histoplasmosis

Many of these disorders may present with additional ocular findings that are distinct from uveitis, as well as evidence of other organ involvement, thereby helping suggest the correct diagnosis.

However, sarcoidosis and Sjögren's disease share similar findings with TINU, making accurate diagnosis difficult in the absence of characteristic involvement of other organs. (See "Kidney disease in primary Sjögren's disease" and "Kidney disease in sarcoidosis" and "Clinical manifestations and diagnosis of sarcoidosis" and "Diagnosis and classification of Sjögren’s disease".)

It may be difficult to distinguish patients with TINU syndrome and late-onset uveitis from those with drug-induced interstitial nephritis (see 'Uveitis' above). A high modified C-reactive protein (mCRP) may help to identify such patients. In the study cited above, among 18 patients with TINU syndrome and late-onset uveitis, compared with 61 patients with drug-induced interstitial nephritis, a high mCRP at the time of kidney biopsy was an independent risk factor for the development of uveitis [3]. In this study, a mCRP of 20.2 percent predicted uveitis with a sensitivity and specificity of 64 and 88 percent, respectively.

MANAGEMENT AND PROGNOSIS

Kidney disease — Kidney disease in patients with TINU is generally believed to be self-limited [34]. In a series of 10 patients, 8 of whom had creatinine clearances of <70 mL/min/1.73 m², kidney function returned to normal levels within one year in all patients [34]. Although seven were administered systemic steroids for uveitis, kidney function recovery was independent of such therapy or the relapse of eye disease.

However, in another series including 25 patients with TINU syndrome, 80 percent had an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² by one year [3]. It is not clear why patients described in this report had such poor outcomes.

Patients with progressive kidney function impairment are typically treated with prednisone at a dose of 1 mg/kg per day (typically between 40 to 60 mg/day). Therapy is given for three to six months (with the duration of therapy dependent upon the response) and then slowly tapered. Most patients recover normal kidney function. This regimen is similar to (but more prolonged than) therapy in acute interstitial nephritis. However, relapses are more likely to occur in TINU syndrome because of the potential immunologic basis of the disease and the lack of a possible culprit agent. (See "Treatment of acute interstitial nephritis".)

Mycophenolate mofetil has been used in a limited number of patients with acute interstitial nephritis and in one reported patient with TINU for the treatment of progressive kidney function impairment [35,36]. (See "Treatment of acute interstitial nephritis".)

The prognosis appears to be dependent upon multiple variables. Some studies have suggested that the degree of tubulointerstitial fibrosis determines prognosis [37]. However, another study suggested that chronicity on biopsy was not correlated with prognosis [3]. In this study of 25 patients, the eGFR at 12 months correlated with age (r = 0.54), presence of thyroid disease (r = 0.44), erythrocyte sedimentation rate (ESR; r = 0.47), leukocyturia (r = 0.45), and serum creatinine at the time of biopsy (r = 0.44). However, no clinical, laboratory, or histologic factors were able to predict a poor outcome. Other data suggest that the prognosis is less favorable in children with TINU [38,39].

Although a few patients with TINU have required kidney replacement therapy, even these patients can expect to only temporarily require dialysis [37].

Uveitis — Topical and systemic corticosteroids have been used for uveitis with success. However, recurrences and relapses of uveitis are common; infrequently, steroid-sparing immunosuppressive agents such as cyclosporine, methotrexate, and mycophenolate mofetil are needed. The optimal management of the patient with uveitis requires early referral to and management by an ophthalmologist. (See "Uveitis: Treatment".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Overview – TINU syndrome is defined by the combination of tubulointerstitial nephritis and uveitis. First described in 1975, most cases have been documented via case reports and small descriptive series. (See 'Introduction' above.)

●Pathogenesis – The pathogenesis of TINU syndrome is unknown. Limited evidence suggests that an autoantigen to modified C-reactive protein (mCRP) may underlie the pathogenesis of the disease. Delayed-type hypersensitivity and suppressed cell-mediated immunity, with a predominance of T lymphocytes, likely also play a significant role. Proliferation and activation of T lymphocytes by interleukin-2 (IL-2) have been implicated. (See 'Pathogenesis' above.)

●Epidemiology – Most patients with TINU are adolescents and young women, although it has been reported in adults and older adults. There is a female-to-male predominance, with no particular racial affinity. Reported risk factors and associations include (see 'Epidemiology' above and 'Risk factors and associations' above):

•HLA-DQA1*01, HLA-DQB1*05, and HLA-DRB1*01

•Prior infection or the use of specific drugs (antibiotics and nonsteroidal antiinflammatory drugs [NSAIDs])

•The Chinese herb "goreisan"

•Concurrent Chlamydia and Epstein-Barr virus infection

•Autoimmune diseases like hypoparathyroidism, thyroid disease, immunoglobulin G4 (IgG4)-related autoimmune disease, and rheumatoid arthritis.

●Clinical and laboratory manifestations – TINU may be associated with systemic findings including fever, weight loss, fatigue, malaise, anorexia, asthenia, abdominal and flank pain, arthralgias, myalgias, headache, polyuria, and/or nocturia. (See 'Clinical and laboratory manifestations' above.)

•Renal manifestations include flank pain, sterile pyuria, hematuria, proteinuria (usually subnephrotic range), kidney function impairment, and acute kidney injury (AKI). Proximal and distal tubular defects can be seen, resulting in aminoaciduria, glucosuria, phosphaturia, and acidification defects. Kidney sonography may demonstrate marked swelling of the kidneys. (See 'Kidney manifestations' above.)

•Patients with uveitis usually present with bilateral eye pain or redness accompanied by photophobia and decreased visual acuity, usually after the onset of kidney disease. (See 'Uveitis' above.)

•Laboratory findings include eosinophilia, anemia, slightly abnormal liver function tests, and an elevated erythrocyte sedimentation rate (ESR). TINU syndrome has been associated with antineutrophil cytoplasmic antibody (ANCA); antinuclear antibody (ANA), an autoantibody directed against renal tubular cells; rheumatoid factor (RF); and hypocomplementemia. (See 'Laboratory findings' above.)

●Diagnosis – The diagnosis of TINU syndrome is suggested by the combination of uveitis and kidney involvement, with kidney biopsy consistent with acute interstitial nephritis. The differential diagnosis includes sarcoidosis, Sjögren's disease, systemic lupus erythematosus, granulomatosis with polyangiitis, Behçet syndrome, and infectious diseases such as tuberculosis, brucellosis, toxoplasmosis, and histoplasmosis. The distinction of TINU syndrome from sarcoidosis and Sjögren's disease is particularly difficult. (See 'Diagnosis and histologic findings' above and 'Differential diagnosis' above.)

●Management and prognosis – Kidney disease in patients with TINU is usually variable. Patients with progressive kidney function impairment are typically treated with prednisone at a dose of 1 mg/kg per day (typically between 40 to 60 mg/day) for three to six months (with the duration of therapy dependent upon the response) and then slowly tapered. The optimal management of the patient with uveitis requires early referral to and management by an ophthalmologist. (See 'Management and prognosis' above and 'Uveitis' above and "Uveitis: Treatment".)