Department of Gastroenterology, Hepatology and EndocrinologyHannover Medical SchoolHannoverGermany.
Chronix BiomedicalGoettingenGermany.
Liver Transpl. 2022 Dec;28(12):1911-1919. doi: 10.1002/lt.26479. Epub 2022 May 9.
Personalized immunosuppression (IS) promises to improve the balance of necessary control of alloreactivity and dose-dependent adverse effects of long-term IS such as kidney insufficiency, infections, and malignancies. The majority of liver transplantation (LT) recipients exhibit graft injuries (graft inflammation and/or fibrosis) that are not eligible for an IS reduction according to current Banff criteria, even when liver enzymes are normal or only marginally elevated. This cross-sectional study evaluated the noninvasive prediction of such subclinical graft injuries in surveillance liver biopsies via donor-derived cell-free DNA (dd-cfDNA). Absolute and fractional dd-cfDNA increased stepwise from patients without histological signs of rejection (n = 26) over subclinical graft injury (n = 61), including subclinical T cell-mediated rejection to clinical overt T cell-mediated rejection (n = 21). Thus, fractional plasma dd-cfDNA was significantly elevated paired to surveillance biopsies with relevant subclinical graft injury according to 2016 Banff criteria compared with those with minimal or absent histological graft injury. In contrast, the presence of donor-specific anti-human leukocyte antigen antibodies was not associated with the amount of dd-cfDNA. The sensitivity and specificity of fractional dd-cfDNA to noninvasively predict relevant subclinical graft injury was rather limited with 73% and 52% at the cutoff value of 2.1% fractional dd-cfDNA. The positive predictive value of fractional dd-cfDNA above 2.1% was 76% to noninvasively predict subclinical graft injury, calculated on the prevalence of graft injury in our prospective surveillance biopsy program, whereas the negative predictive values was not predictive (47%). In conclusion, dd-cfDNA has a rather limited diagnostic fidelity in addition to other noninvasive markers for the assessment of subclinical graft injury in personalized IS approaches after LT in a cross-sectional setting.
个性化免疫抑制（IS）有望改善对同种异体反应的必要控制的平衡，并降低长期 IS 的剂量依赖性不良反应，如肾功能不全、感染和恶性肿瘤。大多数肝移植（LT）受者表现出移植物损伤（移植物炎症和/或纤维化），根据当前的 Banff 标准，即使肝酶正常或仅略有升高，也不符合减少 IS 的条件。这项横断面研究通过供体无细胞游离 DNA（dd-cfDNA）评估了监测肝活检中这种亚临床移植物损伤的非侵入性预测。绝对和分数 dd-cfDNA 从没有组织学排斥迹象的患者（n=26）逐渐增加到亚临床移植物损伤（n=61），包括亚临床 T 细胞介导的排斥反应到临床明显的 T 细胞介导的排斥反应（n=21）。因此，与组织学上最小或无移植物损伤的监测活检相比，根据 2016 年 Banff 标准，与相关亚临床移植物损伤配对的血浆 dd-cfDNA 分数明显升高。相比之下，供体特异性抗人类白细胞抗原抗体的存在与 dd-cfDNA 的量无关。分数 dd-cfDNA 对非侵入性预测相关亚临床移植物损伤的敏感性和特异性相当有限，在 2.1%分数 dd-cfDNA 的截止值下为 73%和 52%。分数 dd-cfDNA 高于 2.1%时，对非侵入性预测亚临床移植物损伤的阳性预测值为 76%，根据我们前瞻性监测活检计划中的移植物损伤患病率计算，而阴性预测值没有预测意义（47%）。总之，除了其他非侵入性标志物外，dd-cfDNA 在 LT 后个性化 IS 方法中评估亚临床移植物损伤的诊断准确性有限。
