Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.
Histocompatibility and Immunogenetics Laboratory, Belgian Red Cross-Flanders, Mechelen, Belgium.
Front Immunol. 2022 Feb 16;13:809059. doi: 10.3389/fimmu.2022.809059. eCollection 2022.
Many kidney allografts fail due to the occurrence of antibody-mediated rejection (ABMR), related to donor-specific anti-HLA antibodies (HLA-DSA). However, the histology of ABMR can also be observed in patients without HLA-DSA. While some non-HLA antibodies have been related to the histology of ABMR, it is not well known to what extent they contribute to kidney allograft injury. Here we aimed to investigate the role of 82 different non-HLA antibodies in the occurrence of histology of ABMR after kidney transplantation.
We included all patients who underwent kidney transplantation between 2004-2013 in a single center and had biobanked serum. Pre- and post-transplant sera (n=2870) were retrospectively tested for the presence of 82 different non-HLA antibodies using a prototype bead assay on Luminex (). A ratio was calculated between the measured MFI value and the cut-off MFI defined by the vendor for each non-HLA target.
874 patients had available pretransplant sera and were included in this analysis. Of them, 133 (15.2%) received a repeat kidney allograft, and 100 (11.4%) had pretransplant HLA-DSA. In total, 204 (23.3%) patients developed histology of ABMR after kidney transplantation. In 79 patients (38.7%) the histology of ABMR was explained by pretransplant or HLA-DSA. The multivariable Cox analysis revealed that only the broadly non-HLA sensitized (number of positive non-HLA antibodies) patients and those with the highest total strength of the non-HLA antibodies (total ratios of the positive non-HLA antibodies) were independently associated with increased rates of histology of ABMR after transplantation. Additionally, independent associations were found for antibodies against TUBB (HR=2.40; 95% CI 1.37 - 4.21, p=0.002), Collagen III (HR=1.67; 95% CI 1.08 - 2.58, p=0.02), VCL (HR=2.04; 95% CI 1.12 - 3.71, p=0.02) and STAT6 (HR=1.47; 95% CI 1.01 - 2.15, p=0.04). The overall posttransplant non-HLA autoreactivity was not associated with increased rates of ABMRh.
This study shows that patients highly and broadly sensitized against non-HLA targets are associated with an increased risk of ABMR histology after kidney transplantations in the absence of HLA-DSA. Also, some pretransplant non-HLA autoantibodies are individually associated with increased rates of ABMR histology. However, whether these associations are clinically relevant and represent causality, warrants further studies.
许多肾移植因抗体介导的排斥反应（ABMR）而失败，这与供体特异性抗 HLA 抗体（HLA-DSA）有关。然而，ABMR 的组织学也可在没有 HLA-DSA 的患者中观察到。虽然一些非 HLA 抗体与 ABMR 的组织学有关，但尚不清楚它们在多大程度上导致了肾移植损伤。在这里，我们旨在研究 82 种不同的非 HLA 抗体在肾移植后发生 ABMR 组织学中的作用。
我们纳入了 2004 年至 2013 年间在单中心接受肾移植且有生物样本库血清的所有患者。使用 Luminex 上的原型珠试验（）对 2870 例回顾性检测了 82 种不同的非 HLA 抗体的存在情况。针对每个非 HLA 靶标，我们计算了测量的 MFI 值与供应商定义的截止 MFI 值之间的比值。
874 例患者有可用的移植前血清，纳入本分析。其中，133 例（15.2%）接受了重复肾移植，100 例（11.4%）移植前有 HLA-DSA。总共 204 例（23.3%）患者在肾移植后发生了 ABMR 的组织学变化。在 79 例患者（38.7%）中，ABMR 的组织学变化可由移植前或 HLA-DSA 解释。多变量 Cox 分析显示，只有广泛非 HLA 致敏（阳性非 HLA 抗体数量）的患者和非 HLA 抗体总强度最高（阳性非 HLA 抗体的总比值）的患者与移植后 ABMR 组织学的发生率增加独立相关。此外，还发现了针对 TUBB（HR=2.40；95%CI 1.37-4.21，p=0.002）、胶原 III（HR=1.67；95%CI 1.08-2.58，p=0.02）、VCL（HR=2.04；95%CI 1.12-3.71，p=0.02）和 STAT6（HR=1.47；95%CI 1.01-2.15，p=0.04）的非 HLA 自身抗体的独立关联。移植后非 HLA 自身反应性的总体情况与 ABMRh 的发生率增加无关。
本研究表明，在不存在 HLA-DSA 的情况下，高度广泛针对非 HLA 靶标的致敏患者与肾移植后 ABMR 组织学风险增加相关。此外，一些移植前的非 HLA 自身抗体与 ABMR 组织学的发生率增加有关。然而，这些关联是否具有临床意义并代表因果关系，还需要进一步研究。
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