<i>HLA-DQA1</i>, <i>-DQB1</i>, and <i>-DRB1</i> Alleles Associated with Acute Tubulointerstitial Nephritis in a Chinese Population: A Single-Center Cohort Study

Abstract

Acute tubulointerstitial nephritis (ATIN) is a common cause of acute kidney injury with various origins. <i>HLA-DQA1</i>, <i>-DQB1</i>, and <i>-DRB1</i> have been associated with development of tubulointerstitial nephritis and uveitis (TINU) syndrome in case reports and small case series, but information about HLA genetic susceptibility to drug hypersensitivity-related ATIN (D-ATIN) or other types of ATIN is limited. In this article, we genotyped 154 patients with ATIN of different causes and 200 healthy controls at <i>HLA-DQA1</i>, <i>-DQB1</i>, and -<i>DRB1</i> loci. We found that there was no difference between patients with D-ATIN and TINU in the carrier's frequency of <i>HLA-DQA1</i>, <i>-DQB1</i>, or <i>-DRB1</i> Patients with Sjogren's syndrome-ATIN and IgG4-related ATIN presented a different pattern of tested HLA alleles. <i>HLA-DQA1*0104</i> (<i>p</i> value corrected by false discovery rate method [<i>Pc</i>] = 4.72 × 10^-22, odds ratio [OR] = 13.81), <i>-DQB1*0503</i> (<i>Pc</i> = 1.95 × 10^-14, OR = 9.51), and <i>-DRB1*1405</i> (<i>Pc</i> = 8.06 × 10^-19, OR = 12.80) were significant risk alleles for the occurrence of D-ATIN and TINU. There were no significant associations between tested HLA alleles and ATIN induced by other causes. Patients with D-ATIN/TINU carrying <i>HLA-DQA1*0104</i>/<i>DQB1*0503</i>/<i>DRB1*1405</i> had higher peak serum creatinine and more severe renal tubulointerstitial inflammatory impairment. They also had significantly higher levels of tubular HLA-DR and HLA-DQ expression, which were correlated with the numbers of interstitial CD4⁺ T lymphocytes (<i>r</i> = 0.975, <i>p</i> < 0.001 and <i>r</i> = 0.832, <i>p</i> = 0.005, respectively) and monocytes/macrophages (<i>r</i> = 0.721, <i>p</i> = 0.004 and <i>r</i> = 0.615, <i>p</i> = 0.02, respectively). In conclusion, patients with D-ATIN or TINU have genetic susceptibility in <i>HLA</i>-<i>DQA1</i>, -<i>DQB1</i>, and -<i>DRB1</i> alleles. <i>HLA-DQA1*0104/DQB1*0503/DRB1*1405</i> serves as a significant risk haplotype for development of D-ATIN and TINU, which might facilitate renal tubulointerstitial inflammation by enhancing Ag-presenting capacity of renal tubular cells.