Tubulointerstitial Nephritis With Uveitis

Clinical Features

Dobrin et al. (1975) described 2 adolescent female patients with tubulointerstitial nephritis and uveitis (TINU); noncaseating granulomas were present in bone marrow in both and in lymph nodes in one.

Gianviti et al. (1994) reported monozygotic female twins who developed acute tubulointerstitial nephritis (ATIN), with identical histologic features and similar clinical symptoms, 1 year apart. Both patients presented with acute renal failure; only 1 developed bilateral uveitis after the onset of nephritis.

Zaoutis et al. (1999) reported a child with TINU whose father had Vogt-Koyanagi-Harada syndrome, an autoimmune-mediated meningoencephalitis with panuveitis.

Gorrono-Echebarria et al. (2001) reported 3 affected adult females and stated that some 50 cases (35 pediatric and 15 adult) of TINU had been described since the initial report of Dobrin et al. (1975). The disorder typically occurs in girls aged 10 to 14 years. The kidneys are affected by tubulointerstitial nephritis with predominantly mononuclear infiltrate in most cases. The ocular lesion principally consists of anterior uveitis and, rarely, panuveitis.

Diagnosis

In a prospective cohort study of 45 patients with uveitis, aged 22 years or younger, Hettinga et al. (2015) found that 18 (40%) had elevated urinary beta-2-microglobulin (B2M; 109700) levels, and 10 (22%) had elevated serum creatinine levels. Twenty of 43 (47%) had proteinuria, and 8 of 45 had renal dysfunction suggesting acute interstitial nephritis. Of those 8, 2 had biopsy-confirmed TINU and 6 fulfilled the criteria for probable TINU. All 8 patients had higher urinary B2M levels than patients with normal renal function. Hettinga et al. (2015) suggested that urinary B2M and serum creatinine levels are sensitive and relatively simple diagnostic screening tools for detecting renal dysfunction and diagnosing TINU in young patients with uveitis.

Pathogenesis

Manjon et al. (1999) reported laboratory findings suggesting that TINU is a cell-mediated immune disease.

HLA Associations

HLA alleles have been implicated as susceptibility factors for TINU. Gafter et al. (1993) found the HLA-DR6 antigen in 3 of 4 TINU patients.

Morino et al. (1991) reported ATIN in 2 sisters, with concomitant recurrent uveitis in 1. Both patients had identical HLA haplotypes and also suffered from mild chronic sialoadenitis. Renal biopsy of the elder sister showed immunoglobulin-containing mononuclear cell interstitial infiltration and immunocomplex-related glomerulonephritis. The younger sister had immune complexes in serum. The authors stated that glomerulonephritis and uveitis might be secondary phenomena of ATIN with circulating immune complexes. They also noted that once uveal involvement has occurred, uveitis may relapse without any renal manifestations.

Levinson et al. (2003) used HLA genotyping to identify genetic markers for TINU, which they found was strongly associated with HLA-DQA1*01, HLA-DQB1*05, and HLA-DRB1*01 in their patient populations. Based on their results and those of previous reports, the authors concluded that the alpha-beta dimer encoded by HLA-DQA1*01/DQB1*05 may be particularly important in conferring risk for development of the disease. The authors noted that it was not known whether TINU and ATIN without uveitis are different presentations of the same disease.

Mackensen et al. (2011) performed an analysis of HLA-DRB1 variants in 28 subjects with isolated bilateral sudden-onset uveitis (as in the TINU subtype) and 14 with isolated tubulointerstitial nephritis (TIN), and compared allele frequencies with a group of normal published controls (European dbMHC) and a published TINU cohort of 18 individuals (Levinson et al., 2003). They found a significantly higher frequency of HLA-DRB1*0102 in the isolated uveitis cohort versus normal controls (10.7% vs. 0.6%). None of the nephritis patients showed this HLA subtype. Another association, with HLA-DRB1*08, was seen in the isolated uveitis cohort, with an allele frequency of 10.7% versus 2.7% in normal controls. In contrast, frequency of the HLA-DRB1*08 allele was not different between controls and the TINU cohort (allele frequency 2.8%). Mackensen et al. (2011) concluded that the incidence of HLA-DRB1*0102 was increased in sudden-onset bilateral anterior uveitis, as seen in patients with TINU. As the same allele did not appear to occur in increased frequency in patients with isolated TIN, HLA-DRB1*0102 might predispose to this sudden subset of uveitis.