Background The development of antibodies specific to HLA expressed on donor tissue (donor-specific antibodies [DSAs]) is a prominent risk factor for kidney graft loss. Non-HLA antibodies with pathogenic potential have also been described, including natural antibodies (Nabs). These IgG Nabs bind to immunogenic self-determinants, including oxidation-related antigens.

Methods To examine the relationship of Nabs with graft outcomes, we assessed Nabs in blinded serum specimens collected from a retrospective cohort of 635 patients who received a transplant between 2005 and 2010 at Necker Hospital in Paris, France. Serum samples were obtained immediately before transplant and at the time of biopsy-proven rejection within the first year or 1 year after transplant. Nabs were detected by ELISA through reactivity to the generic oxidized epitope malondialdehyde.

Results Univariate Cox regression analysis identified the development of post-transplant Nabs (defined as 50% increase in reactivity to malondialdehyde) as a significant risk factor for graft loss (hazard ratio, 2.68; 95% confidence interval, 1.49 to 4.82; P=0.001). Post-transplant Nabs also correlated with increased mean Banff scores for histologic signs of graft injury in post-transplant biopsy specimens. Multivariable Cox analyses confirmed Nabs development as a risk factor independent from anti-HLA DSAs (hazard ratio, 2.07; 95% confidence interval, 1.03 to 4.17; P=0.04). Moreover, patients with Nabs and DSAs had a further increased risk of kidney graft loss.

Conclusions These findings reveal an association between Nabs, kidney graft injury, and eventual graft failure, suggesting the involvement of Nabs in immune mechanisms of rejection.

背景技术对供体组织上表达的HLA特异性抗体（供体特异性抗体[DSA]）的开发是造成肾移植物丢失的重要危险因素。还已经描述了具有致病潜力的非HLA抗体，包括天然抗体（Nabs）。这些IgG Nab与免疫原性自决定簇结合，包括与氧化有关的抗原。

方法为了检查Nabs与移植物预后的关系，我们评估了2005年至2010年在法国巴黎Necker医院接受移植的635例患者的回顾性队列中收集的盲血清标本中的Nabs。在移植前和移植后的第一年或一年内，在移植前和活检证实排斥的同时获取血清样品。通过与通用氧化表位丙二醛的反应性，通过ELISA检测到小b。

结果单因素Cox回归分析确定了移植后Nabs的发育（定义为对丙二醛的反应性增加了50％）是造成移植物损失的重要危险因素（危险比，2.68; 95％置信区间，1.49至4.82; P = 0.001 ）。移植后的Nabs也与移植后活检标本中移植物损伤的组织学标志的平均Banff评分增加有关。多变量Cox分析证实，Nabs的发展是独立于抗HLA DSA的危险因素（危险比2.07； 95％置信区间1.03至4.17；P = 0.04）。此外，Nabs和DSA的患者肾脏移植物丢失的风险进一步增加。

结论这些发现揭示了Nabs与肾移植物损伤和最终的移植失败之间的关联，这表明Nabs参与了排斥反应的免疫机制。