Konduri Anusha, Flynn Kathryn E, Huebschman Ashley, Crandall Bronwyn, Sinicropi Natalie, Giacobbe Bethany, Zamberlan Mary, Najor Matthew, Cusick Matthew, Lim Heang M, McCormick Amanda D, Schumacher Kurt R, Peng David M
University of Michigan, Ann Arbor, Michigan, USA.
Pediatr Transplant. 2025 Sep;29(6):e70168. doi: 10.1111/petr.70168.
Antibody-mediated rejection (AMR) remains a significant complication following heart transplantation, contributing to graft dysfunction and reduced survival. Donor-derived cell-free DNA (dd-cfDNA) is emerging as a non-invasive biomarker for detecting and monitoring graft injury, correlating with episodes of rejection and response to treatment. Daratumumab, an anti-CD38 monoclonal antibody targeting plasma cells, has shown promise in treating AMR. We present a case series of pediatric and young adult heart transplant recipients demonstrating donor-derived cell-free DNA's potential utility in monitoring for AMR and the effect of therapies including daratumumab.
We report five cases showing that elevated dd-cfDNA correlated with pathological AMR (pAMR), and treatment with daratumumab improved both pAMR and dd-cfDNA levels. Most of our patients had persistently elevated donor-specific antibody (DSA) as observed by MFI values; however, there was a reduction in DSA titer that corresponded with improvement in pAMR and dd-cfDNA levels. Recurrent increases in dd-cfDNA were also useful in guiding the need for repeat treatment with daratumumab. Although DSA levels often remained elevated despite histologic improvement, decreasing dd-cfDNA levels correlated more closely with the resolution of AMR.
In this case series of pediatric and young adult heart transplant recipients, our findings suggest that dd-cfDNA can serve as a valuable biomarker for diagnosing AMR and treatment response, which are not often reflected by DSA MFI alone. Our dd-cfDNA data supports the efficacy of daratumumab in treating AMR and may guide the need for ongoing treatment. Further studies are warranted to validate these findings and establish guidance for the use of daratumumab and dd-cfDNA in this patient population.
抗体介导的排斥反应（AMR）仍是心脏移植后一个重要的并发症，会导致移植物功能障碍并降低生存率。供体来源的游离DNA（dd-cfDNA）正逐渐成为一种用于检测和监测移植物损伤的非侵入性生物标志物，与排斥反应发作及治疗反应相关。达雷妥尤单抗是一种靶向浆细胞的抗CD38单克隆抗体，在治疗AMR方面已显示出前景。我们展示了一系列儿科和年轻成人心脏移植受者的病例，证明了供体来源的游离DNA在监测AMR以及包括达雷妥尤单抗在内的治疗效果方面的潜在效用。
我们报告了5例病例，显示dd-cfDNA升高与病理AMR（pAMR）相关，达雷妥尤单抗治疗改善了pAMR和dd-cfDNA水平。我们的大多数患者通过平均荧光强度（MFI）值观察到供体特异性抗体（DSA）持续升高；然而，DSA滴度有所降低，这与pAMR和dd-cfDNA水平的改善相对应。dd-cfDNA的反复升高也有助于指导是否需要重复使用达雷妥尤单抗进行治疗。尽管组织学改善后DSA水平通常仍保持升高，但dd-cfDNA水平的降低与AMR的缓解更密切相关。
在这个儿科和年轻成人心脏移植受者的病例系列中，我们的研究结果表明，dd-cfDNA可作为诊断AMR和治疗反应的有价值生物标志物，而这通常不能仅由DSA MFI反映出来。我们的dd-cfDNA数据支持达雷妥尤单抗治疗AMR 的疗效，并可能指导持续治疗的必要性。有必要进行进一步研究以验证这些发现，并为在该患者群体中使用达雷妥尤单抗和dd-cfDNA建立指导原则。
