Sapir-Pichhadze Ruth, Zhang Xun, Ferradji Abdelhakim, Madbouly Abeer, Tinckam Kathryn J, Gebel Howard M, Blum Daniel, Marrari Marilyn, Kim S Joseph, Fingerson Stephanie, Bashyal Pradeep, Cardinal Héloïse, Foster Bethany J
Division of Nephrology, Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada; The Multi Organ Transplant Program, Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada; Centre for Outcomes Research and Evaluation (CORE), McGill University Health Centre, Montreal, Quebec, Canada; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada.
Centre for Outcomes Research and Evaluation (CORE), McGill University Health Centre, Montreal, Quebec, Canada.
Kidney Int. 2020 Apr;97(4):778-785. doi: 10.1016/j.kint.2019.10.028. Epub 2019 Nov 12.
To optimize strategies that mitigate the risk of graft loss associated with HLA incompatibility, we evaluated whether sequence defined HLA targets (eplets) that result in donor-specific antibodies are associated with transplant outcomes. To define this, we fit multivariable Cox proportional hazard models in a cohort of 118 382 United States first kidney transplant recipients to assess risk of death-censored graft failure by increments of ten antibody-verified eplet mismatches. To verify robustness of our findings, we conducted sensitivity analysis in this United States cohort and assessed the role of antibody-verified eplet mismatches as autonomous predictors of transplant glomerulopathy in an independent Canadian cohort. Antibody-verified eplet mismatches were found to be independent predictors of death-censored graft failure with hazard ratios of 1.231 [95% confidence interval 1.195, 1. 268], 1.268 [1.231, 1.305] and 1.411 [1.331, 1.495] for Class I (HLA-A, B, and C), -DRB1 and -DQB1 loci, respectively. To address linkage disequilibrium between HLA-DRB1 and -DQB1, we fit models in a subcohort without HLA-DQB1 eplet mismatches and found hazard ratios for death-censored graft failure of 1.384 [1.293, 1.480] for each additional antibody-verified HLA-DRB1 eplet mismatch. In a subcohort without HLA-DRB1 mismatches, the hazard ratio was 1.384 [1.072, 1.791] for each additional HLA-DQB1 mismatch. In the Canadian cohort, antibody-verified eplet mismatches were independent predictors of transplant glomerulopathy with hazard ratios of 5.511 [1.442, 21.080] for HLA-DRB1 and 3.640 [1.574, 8.416] for -DRB1/3/4/5. Thus, donor-recipient matching for specific HLA eplets appears to be a feasible and clinically justifiable strategy to mitigate risk of graft loss.
为优化降低与HLA不相容性相关的移植物丢失风险的策略，我们评估了导致供体特异性抗体产生的序列定义的HLA靶点（表位）是否与移植结果相关。为明确这一点，我们在118382名美国初次肾移植受者队列中拟合多变量Cox比例风险模型，以通过每增加10个经抗体验证的表位错配来评估死亡截尾的移植物失败风险。为验证我们研究结果的稳健性，我们在美国队列中进行了敏感性分析，并在一个独立的加拿大队列中评估经抗体验证的表位错配作为移植性肾小球病自主预测指标的作用。结果发现，经抗体验证的表位错配是死亡截尾的移植物失败的独立预测指标，I类（HLA - A、B和C）、- DRB1和 - DQB1基因座的风险比分别为1.231 [95%置信区间1.195, 1.268]、1.268 [1.231, 1.305]和1.411 [1.331, 1.495]。为解决HLA - DRB1和 - DQB1之间的连锁不平衡问题，我们在一个没有HLA - DQB1表位错配的亚队列中拟合模型，发现每增加一个经抗体验证的HLA - DRB1表位错配，死亡截尾的移植物失败的风险比为1.384 [1.293, 1.480]。在一个没有HLA - DRB1错配的亚队列中，每增加一个HLA - DQB1错配，风险比为1.384 [1.072, 1.791]。在加拿大队列中，经抗体验证的表位错配是移植性肾小球病的独立预测指标，HLA - DRB1的风险比为5.511 [1.442, 21.080]，- DRB1/3/4/5的风险比为3.640 [1.574, 8.416]。因此，供受者特定HLA表位匹配似乎是一种可行且临床上合理的降低移植物丢失风险的策略。
