循环供体特异性抗 HLA 抗体是导致移植物早期和加速纤维化的主要因素。
Circulating donor-specific anti-HLA antibodies are a major factor in premature and accelerated allograft fibrosis.
机构信息
Paris Translational Research Center for Organ Transplantation, Institut national de la santé et de la recherche médicale, Unité mixte de recherche-S970, Paris, France; Department of Pathology, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
Paris Translational Research Center for Organ Transplantation, Institut national de la santé et de la recherche médicale, Unité mixte de recherche-S970, Paris, France; Department of Nephrology and Kidney Transplantation, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
出版信息
Kidney Int. 2017 Sep;92(3):729-742. doi: 10.1016/j.kint.2017.03.033. Epub 2017 May 26.
Addressing the causes of kidney allograft-accelerated aging is an important challenge for improving long-term transplant outcomes. Here we investigated the role of circulating donor-specific anti-HLA antibodies (HLA-DSAs) in the development and the progression of kidney allograft fibrosis with inclusion of traditional risk factors for allograft fibrosis. We prospectively enrolled 1539 consecutive kidney recipients transplanted in two centers and assessed interstitial fibrosis and tubular atrophy (IF/TA) in biopsies performed at one year post-transplantation. The HLA-DSAs and all traditional determinants of IF/TA were recorded at transplantation and within the first year post-transplantation, including histological diagnoses in 2260 "for cause" biopsies. This identified 498 (32%) patients with severe IF/TA (Banff IF/TA grade 2 or more). HLA-DSAs were significantly associated with severe IF/TA (adjusted odds ratio, 1.53; 95% confidence interval 1.16-2.01) after including 37 determinants. HLA-DSAs remained significantly associated with severe IF/TA in patients without antibody-mediated rejection (adjusted odds ratio 1.54; 1.11-2.14). HLA-DSAs were the primary contributor, being involved in 11% of cases, while T cell-mediated rejection, calcineurin-inhibitor toxicity, acute tubular necrosis, pyelonephritis, and BK virus-associated nephropathy were involved in 9%, 8%, 6%, 5%, and 4% of cases, respectively. One hundred fifty-four patients with HLA-DSA-associated severe IF/TA showed significantly increased microvascular inflammation, transplant glomerulopathy, C4d deposition in capillaries, and decreased allograft survival compared to 344 patients with severe IF/TA without HLA-DSAs. Three hundred seventy-eight patients with post-transplant HLA-DSAs exhibited significantly accelerated progression of IF/TA compared to 1161 patients without HLA-DSAs in the biopsies performed at one year post-transplant and beyond. Thus, circulating HLA-DSAs are major determinants of premature and accelerated allograft fibrosis acting independently of traditional risk factors and antibody-mediated rejection.
解决导致肾移植加速老化的原因是改善长期移植结果的重要挑战。在这里，我们研究了循环供体特异性抗 HLA 抗体（HLA-DSAs）在包括移植纤维化传统危险因素在内的肾移植纤维化发展和进展中的作用。我们前瞻性纳入了在两个中心接受移植的 1539 例连续肾移植受者，并在移植后 1 年进行的活检中评估了间质纤维化和肾小管萎缩（IF/TA）。在移植时和移植后 1 年内记录了 HLA-DSAs 和所有 IF/TA 的传统决定因素，包括 2260 例“因原因”活检的组织学诊断。这确定了 498 例（32%）严重 IF/TA（Banff IF/TA 分级 2 或更高）患者。包括 37 个决定因素后，HLA-DSAs 与严重 IF/TA 显著相关（调整优势比，1.53；95%置信区间 1.16-2.01）。在没有抗体介导排斥反应的患者中，HLA-DSAs 与严重 IF/TA 仍显著相关（调整优势比，1.54；1.11-2.14）。HLA-DSAs 是主要的贡献者，占 11%，而 T 细胞介导的排斥反应、钙调神经磷酸酶抑制剂毒性、急性肾小管坏死、肾盂肾炎和 BK 病毒相关性肾病分别占 9%、8%、6%、5%和 4%。与 344 例无 HLA-DSA 的严重 IF/TA 患者相比，154 例 HLA-DSA 相关严重 IF/TA 患者的微血管炎症、移植肾小球病、毛细血管中 C4d 沉积和移植物存活率明显增加。与 1161 例无 HLA-DSA 的患者相比，移植后 HLA-DSAs 的 378 例患者在移植后 1 年及以后的活检中 IF/TA 进展明显加快。因此，循环 HLA-DSAs 是导致同种异体移植纤维化过早和加速的主要决定因素，独立于传统危险因素和抗体介导的排斥反应。
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