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HLA Alleles and Prognosis of PLA2R-Related Membranous Nephropathy
Wei-Bo Le1, Jing-Song Shi1, Yang Fan1
1National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
Background And Objectives:
Associations between HLA alleles and susceptibility to M-type phospholipase A2 receptor (PLA2R)-related membranous nephropathy have been well defined previously in Chinese patients. However, the relationships between HLA alleles and kidney outcome remain unclear.
Design, Setting, Participants, & Measurements:
Five HLA genes (DRB1, DQA1, DQB1, DRB3, and DRB5) were genotyped in a prospective cohort of 392 patients with PLA2R-related membranous nephropathy. The associations between HLA alleles and kidney outcomes were studied.
Results:
A total of 79 HLA alleles were identified in this study. Four HLA alleles, DRB1*13:01 (n=12; hazard ratio, 3.7; 95% confidence interval, 1.8 to 7.8; P<0.001), DQB1*06:03 (n=12; hazard ratio, 3.7; 95% confidence interval, 1.8 to 7.8; P<0.001), DRB1*04:05 (n=12; hazard ratio, 3.8; 95% confidence interval, 1.5 to 9.5; P=0.004), and DQB1*03:02 (n=21; hazard ratio, 3.1; 95% confidence interval, 1.4 to 6.7; P=0.005), were associated with a ≥40% eGFR decline during follow-up. DRB1*13:01 and DQB1*06:03 were tightly linked with each other. Forty-four of the 392 patients (11%) carried at least one of the four identified risk HLA alleles in this study. Compared with patients who were negative for all risk HLA alleles, those carrying at least one risk HLA allele had a significant risk of a ≥40% eGFR decline during follow-up (hazard ratio, 3.9; 95% confidence interval, 2.3 to 6.7; P<0.001). After adjusting for age, sex, proteinuria, albumin, eGFR, and anti-PLA2R antibody levels, multivariable Cox analysis showed that patients carrying any of the four risk HLA alleles remained associated with a higher risk of a ≥40% decline in eGFR (hazard ratio, 4.1; 95% confidence interval, 2.3 to 7.1; P<0.001).
Conclusions:
Carrying any of the HLA alleles, DRB1*13:01/DQB1*06:03, DRB1*04:05, and DQB1*03:02, was independently associated with poor prognosis in Chinese patients with PLA2R-related membranous nephropathy.
Insights
Certain human leukocyte antigen (HLA) alleles, including DRB1*13:01/DQB1*06:03, DRB1*04:05, and DQB1*03:02, are linked to worse kidney outcomes in patients with phospholipase A2 receptor-related membranous nephropathy.
Area of Science:
- Nephrology
- Immunogenetics
Background:
- PLA2R-related membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults.
- Previous studies identified HLA alleles associated with susceptibility to PLA2R-MN in Chinese populations.
- The impact of specific HLA alleles on kidney outcomes in PLA2R-MN remains largely unknown.
Purpose of the Study:
- To investigate the association between HLA alleles and kidney outcomes in Chinese patients with PLA2R-MN.
- To identify specific HLA alleles that predict a decline in estimated glomerular filtration rate (eGFR).
Main Methods:
- A prospective cohort study involving 392 patients with PLA2R-MN.
- Genotyping of five HLA genes: DRB1, DQA1, DQB1, DRB3, and DRB5.
- Analysis of associations between HLA alleles and a composite endpoint of ≥40% eGFR decline using multivariable Cox regression.
Main Results:
- Four HLA alleles (DRB1*13:01, DQB1*06:03, DRB1*04:05, and DQB1*03:02) were significantly associated with a ≥40% eGFR decline.
- Patients carrying any of these four risk HLA alleles had a 4.1-fold higher risk of significant eGFR decline, independent of other clinical factors.
- DRB1*13:01 and DQB1*06:03 were found to be in strong linkage disequilibrium.
Conclusions:
- Specific HLA alleles, namely DRB1*13:01/DQB1*06:03, DRB1*04:05, and DQB1*03:02, are independently associated with poor kidney prognosis in Chinese patients with PLA2R-MN.
- These findings highlight the potential role of HLA genotyping in predicting disease progression and guiding clinical management.
