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Editor,—An uncommon association between tubulointerstitial nephritis and anterior uveitis was described in two adolescent female patients with non-caseating granulomas in both bone marrow and lymph nodes by Dobrin1 and is referred to as TINU syndrome. Since then, some 50 cases (35 paediatric patients and 15 adults) have been described. Its distribution is typically in young girls aged 10–14 years. The kidneys are affected by tubulointerstitial nephritis with predominant mononuclear infiltrate in the majority of cases. The ocular lesion invariably consists of anterior uveitis and, exceptionally, panuveitis. Although the aetiology is still unknown, the laboratory findings reported suggest that TINU is a cell mediated immune disease.2 Genetic markers (HLA alleles) have also been implicated as susceptibility risk factors.3
We describe the cases of three further female adult patients of Spanish origin who developed acute renal insufficiency secondary to idiopathic acute tubulointerstitial nephritis, and who, several months later, suffered a bilateral acute anterior uveitis. In all three patients, similar laboratory findings were found including slight anaemia, increase of the serum creatinine, blood urea nitrogen, and erythrocyte sedimentation rate. Glycosuria and proteinuria were found in the urinalysis. Hantavirus or hepatitis B, C antibodies were not found. Tuberculin and Bengal rose were negative. ANA, anti-DNA, anti-Sm Anti-RNP, anti-SSA, anti-SSB, and ANCA autoantibodies, detected by indirect immunofluorescence (IFI) or counterimmunoelectrophoresis (CIE), were all negative. RPR, antistreptolysin O, PCR, and rheumatoid factor were also negative. Thyroid function was normal, as were the chest and abdomen x rays and renal ultrasonography. Finally, polyclonal hypergammaglobulinaemia was found. Further details are given in Table 1.The HLA class I and class II phenotype of patients was carried out by a microlymphocytoxicity test and DNA typing techniques, respectively.4 As a control group, 176 unrelated healthy individuals from Madrid were also HLA typed.
The distribution of the frequencies of HLA alleles in both groups was compared using the Fisher test. The aetiological fraction (δ) and the odds ratio (OR) value with the corresponding 95% confidence intervals (CI) was calculated.
In our series, HLA-A24 is found in 67% of the patients, compared with 14% in the Spanish control population (p >0.05, Fisher test). No other HLA class I allele shows a remarkable deviation from the control population. Regarding HLA class II alleles, HLA-DR14 (a HLA-DR6 subtype) is found in two of our patients, whereas it appears in eight of our control individuals (67% v 4%, p=0.006; OR 48.2 (95% CI 5.5–258)). This finding would lend further support to the HLA-DR6 association previously reported in other populations.3 The frequency of other HLA class II alleles is also increased in the diseased group when compared with the control group, although statistical significance is not reached: HLA-DQ5 (100%v 40%, p >0.05, Fisher test) and HLA-DR52 (100% v 56%, p>0.05)
When the aetiological fraction (δ) is considered, HLA-DR52 and HLA-DQ5 show the highest value (δ=1), followed by HLA-DR14 (δ=0.74) and HLA-A24 (δ=0.71).
These data point to HLA class II antigens rather than HLA class I as the main TINU susceptibility markers. It may be worth recalling that HLA class II molecules are expressed in renal epithelial cells or in the uvea when inflamed. Thus, genetically predisposed individuals (that is, HLA-DR14) would be more prone to producing the lesions observed in the TINU syndrome upon activation of the immune system.
We are aware of the limited value of the statistical analysis carried out given the small number of patients studied, but this is inherent to the pathology itself, since scarcely 50 TINU patients have been described worldwide since its first description in 1975. We thus would use HLA phenotyping in future patients to assess the role of these HLA class II antigens in TINU susceptibility.
We are grateful to Dr A Annaiz-Villena (Immunologia Hospital “12 de Octubre,” Madrid) for HLA typing of patients.