HLA-DQA1, -DQB1, and -DRB1 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. HLA-DQA1, -DQB1, and -DRB1 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 HLA-DQA1, -DQB1, and -DRB1 loci. We found that there was no difference between patients with D-ATIN and TINU in the carrier’s frequency of HLA-DQA1, -DQB1, or -DRB1. Patients with Sjogren’s syndrome–ATIN and IgG4-related ATIN presented a different pattern of tested HLA alleles. HLA-DQA1*0104 (p value corrected by false discovery rate method [Pc] = 4.72 × 10−22, odds ratio [OR] = 13.81), -DQB1*0503 (Pc = 1.95 × 10−14, OR = 9.51), and -DRB1*1405 (Pc = 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 HLA-DQA1*0104/DQB1*0503/DRB1*1405 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 (r = 0.975, p < 0.001 and r = 0.832, p = 0.005, respectively) and monocytes/macrophages (r = 0.721, p = 0.004 and r = 0.615, p = 0.02, respectively). In conclusion, patients with D-ATIN or TINU have genetic susceptibility in HLA-DQA1, -DQB1, and -DRB1 alleles. HLA-DQA1*0104/DQB1*0503/DRB1*1405 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.

Tubulointerstitial nephritis and uveitis syndrome in an adolescent female: a case report

“…(2017), Japan [ 45 ] 3 Pt 1: 15-year-old boy with bilateral anterior uveitis Pt 2: 14-year-old girl with bilateral papilledema Pt 3: 49-year-old woman with panuveitis Pt 1: elevated IgG, elevated ESR and CRP, azotemia, elevated urinary β2 microglobulin and NAG Pt 2: normal at initial visit Pt 3: mild increase in serum creatinine Pt 1: biopsy-proven AIN Pt 2: no biopsy approach Pt 3: biopsy-proven AIN 12 months before admission Pt 1: pulse of methylprednisolone 1 g/day for 3 days, tapering of dose Pt 2: topical steroid, triamcinolone acetonide Pt 3: topical and systemic steroid Pt 1: continued topical and oral steroids needed due to relapse Pt 2: no relapse Pt 3: no relapse In addition to anterior uveitis, TINU may present also with fundal features Jia et al . (2018), People’s Republic of China [ 22 ] 38 NA NA All Pt with clinicopathologically diagnosed AIN NA NA Patients with drug-induced AIN or TINU have genetic susceptibility in HLA-DQA1, -DQB1, and DRB1 alleles Provencher et al . (2018), Iowa [ 46 ] 9 9 TINU Pt with iridocyclitis and elevated urinary β-2-microglobulin, 9/9 met full diagnostic criteria Mean urinary β-2 microglobulin at presentation was 6536 μg/L (40.9 times the upper limit of normal); elevated serum creatinine in 7/9 Pt; proteinuria in 5/9 Pt Performed in 3/9 Pt.…”

Drug-Induced Acute Kidney Injury

“…Dendritic cells interspersed between tubular cells recognize these drug-related antigens, migrate to local lymph nodes, and initiate adaptive immune responses (77)(78)(79). Immunemediated kidney injury is orchestrated by various CD4 1 T cell subsets and varies depending on the inciting agent, suggesting that AIN may be the final common pathway of distinct mechanisms of injury (77)(78)(79).…”

Facing the Challenge of Drug-Induced Acute Interstitial Nephritis

“…Histologically, this study showed that there were positive correlations between the number of interstitial CD4+ T lymphocytes and the tubular expression of HLA-DR and HLA-DQ. In the same way, the infiltration of monocytes/macrophages into the interstitial compartment and into the renal tubular wall was closely correlated with the tubular expression of HLA-DR and HLA-DQ [22].…”