BACKGROUND There is significant variability among pathologists in the histopathological interpretation of the endomyocardial biopsy (EMB) for acute cellular rejection (ACR), and assessment of variability in the interpretation of antibody-mediated rejection (AMR) has not been reported. In contemporary practice, the strategy of allograft surveillance with donor-derived cell-free DNA (dd-cfDNA) compared to EMB has not been compared with a focus on long-term clinical outcomes beyond acute rejection (AR). METHODS The Genomic Research Alliance for Transplantation is a multicenter, prospective cohort study that enrolled patients from 2015 to 2020. The center pathologist read was compared to 2 blinded core cardiac pathologists. ACR and AMR were graded based on the International Society for Heart and Lung Transplantation criteria. Weighted Cohen's kappa (κ) was used to evaluate interrater reliability between the center and core reads. To assess long-term outcomes, we evaluated a composite of AR, allograft dysfunction, and mortality within 1 year. RESULTS The study included 94 patients (median age 55 years [interquartile range (IQR) 45, 62]), 30% female sex, 41% Black race), with 429 paired EMBs and dd-cfDNA measures. The concordance rate between center and core pathologists was 77% for ACR (95% confidence interval [CI]: 66%-89%) and 63% for AMR (95% CI: 53%-74%). Forty-six patients had an elevation in dd-cfDNA without AR by EMB. The median dd-cfDNA was 0.49% (IQR: 0.35, 1.01), and subsequent AR, allograft dysfunction, or mortality occurred in 59% of these patients at 1 year. In patients with AR by EMB and negative dd-cfDNA (n = 5), the composite outcome occurred in 20% of patients at 1 year. At baseline, the positive likelihood ratio (LR+) of dd-cfDNA to detect AR by the center pathologist was 3.74 (95% CI 3.01-4.64) and by core pathologist was 2.59 (95% CI: 1.95-3.45). If the composite outcome was included as a true positive, the LR+ of dd-cfDNA improved to 9.82 (95% CI: 7.04-13.69) and 7.63 (95% CI: 5.61-10.38) at 1 year, respectively. CONCLUSIONS Pathologists' interrater reliability is limited in AMR similar to what has been reported in ACR. The LR+ of dd-cfDNA when compared with traditional histopathology is limited, but when longitudinal clinical outcomes are included to assess diagnostic performance, the LR+ improves significantly. The value of dd-cfDNA extends beyond the diagnosis of AR to include other clinically meaningful outcomes for patients after heart transplant.

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代表 GRAfT 研究人员，代表 GRAfT 研究人员，评估者间可靠性和供体来源的游离 DNA 升高的临床意义。


背景 病理学家对急性细胞排斥反应 （ACR） 的心内膜心肌活检 （EMB） 的组织病理学解释存在显着差异，并且尚未报道抗体介导的排斥反应 （AMR） 解释的变异性评估。在当代实践中，与 EMB 相比，使用供体来源的无细胞 DNA （dd-cfDNA） 进行同种异体移植物监测的策略尚未与关注急性排斥反应 （AR） 以外的长期临床结局进行比较。方法 移植基因组研究联盟是一项多中心、前瞻性队列研究，于 2015 年至 2020 年招募了患者。将中心病理学家读数与 2 名盲法核心心脏病病理学家进行了比较。根据国际心肺移植学会 （International Society for Heart and Lung Transplantation） 标准对 ACR 和 AMR 进行分级。加权 Cohen 的 kappa （κ） 用于评估中心读数和核心读数之间的评分者间可靠性。为了评估长期结局，我们评估了 AR、同种异体移植物功能障碍和 1 年内死亡率的综合结果。结果 该研究包括 94 名患者 （中位年龄 55 岁 [四分位距 （IQR） 45， 62]），30% 为女性，41% 为黑人），有 429 个配对的 EMBs 和 dd-cfDNA 测量。ACR 中心和核心病理学家之间的一致性为 77% （95% 置信区间 [CI]： 66%-89%） 和 63% AMR （95% CI： 53%-74%）。46 例患者 EMB 导致 dd-cfDNA 升高，无 AR。中位 dd-cfDNA 为 0.49% （IQR： 0.35， 1.01），随后 59% 的患者在 1 年时发生 AR 、同种异体移植物功能障碍或死亡。在 EMB 和 dd-cfDNA 阴性 （n = 5） 的 AR 患者中，20% 的患者在 1 年时出现复合结果。 基线时，中心病理学家检测 AR 的 dd-cfDNA 阳性似然比 （LR+） 为 3.74 （95% CI 3.01-4.64），核心病理学家为 2.59 （95% CI： 1.95-3.45）。如果将复合结局纳入真阳性，dd-cfDNA 的 LR+ 在 1 年时分别提高到 9.82 （95% CI： 7.04-13.69） 和 7.63 （95% CI： 5.61-10.38）。结论 病理学家在 AMR 中的评分者间信度有限，类似于 ACR 中报道的情况。与传统组织病理学相比，dd-cfDNA 的 LR+ 是有限的，但当包括纵向临床结果以评估诊断性能时，LR+ 显着改善。dd-cfDNA 的价值超越了 AR 的诊断，包括心脏移植后患者其他具有临床意义的结果。