Clinical Utility of Combined Donor-Derived Cell-Free DNA and Peripheral Gene-Expression-Profiling in Heart Transplant Recipients.

IF 1.9 4区医学 Q2 SURGERY

Clinical Transplantation Pub Date : 2025-10-01 DOI:10.1111/ctr.70340

Cathrine M Moeller, Andrea Fernandez Valledor, Daniel Oren, Salwa Rahman, Afsana Rahman, Matthew Regan, Changhee Lee, Adi Hertz, Gal Rubinstein, Julia Baranowska, Boaz Elad, Carolyn Hennecken, Ruben Salazar, Amit Oren, Elena M Donald, Dor Lotan, Kyung T Oh, David Bae, Adil Yunis, David Majure, Melana Yuzefpolskaya, Paolo C Colombo, Jayant K Raikhelkar, Justin A Fried, Ersilia M DeFilippis, Koji Takeda, Kevin J Clerkin, Farhana Latif, Gabriel T Sayer, Nir Uriel

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引用次数: 0

Abstract

Introduction: Donor-derived-cell-free-DNA (dd-cfDNA) and peripheral-gene-expression-profiling (pGEP) are tools for monitoring heart transplant (HT) recipients for rejection. We aimed to assess the combined utility of dd-cfDNA/pGEP in HT recipients.

Methods: We evaluated HT recipients between 2019 and 2023 with a paired dd-cfDNA(AlloSure-AS)/GEP(AlloMap-AM) results (HeartCare-CareDx-CA-USA). Multi-organ-transplant recipients were excluded. Samples were assessed with endomyocardial biopsy <30 days from the day of sample drawn, with rejection defined as ISHLT grade ≥ 1R/1B/pAMR > 0. A positive GEP test score was defined as >30 within 5 months posttransplant and 34 thereafter; a positive dd-cfDNA result was ≥0.12%. Samples were categorized into four groups based on dd-cfDNA/GEP results.

Results: Of the 2388 samples (257 patients) included, 1437 samples (60.2%) were (-)dd-cfDNA/(-)GEP, 419 samples (17.5%) were (-)dd-cfDNA/(+)GEP, 375 samples (15.7%) were (+)dd-cfDNA/(-)GEP, and 157 samples (6.6%) were (+)dd-cfDNA/(+)GEP. The median age was 55 years and 27% were females. The median time from HT to sample was 10 months [IQR 5-18]. The median positive AS level was 0.22% [IQR 0.15-0.48]. Twenty-nine percent of the samples had correlated EMB results, mostly in the (+)dd-cfDNA/(+)GEP group (55%), followed by the discordant groups (+)dd-cfDNA/(-)GEP (49%) and (-)dd-cfDNA/(+)GEP (32%), and the (-)dd-cfDNA/(-)GEP group (20%; p < 0.001). Rejection occurred in 7.1% of samples, with the highest rates in the (+)dd-cfDNA/(+)GEP group (15.1%), followed by the (+)dd-cfDNA/(-)GEP (10.9%), (-)dd-cfDNA/(-)GEP (3.8%), and (-)dd-cfDNA/(+)GEP (3.7%) (p < 0.001) groups. The median follow-up time was 29 months [IQR 16-42]. The (+)dd-cfDNA/(+)GEP group demonstrated an increased risk of mortality (HR: 6.1, 95% CI [2.5-14.8]; p < 0.001) compared to (-)dd-cfDNA/(-)GEP group. Similarly the (+)dd-cfDNA/(-)GEP group demonstrated an almost 6-fold risk of mortality (HR: 5.6, 95% CI [1.8-17.5]; p = 0.003).

Conclusions: Patients with (+)dd-cfDNA/(+)GEP result were more frequently biopsied and had higher rates of rejection. This group exhibited a six-fold increased risk of mortality and a seven-fold increased risk of mortality at dd-cfDNA thresholds of 0.12% and 0.20%, respectively, compared to the negative concordant group.

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供体来源的无细胞DNA和外周基因表达谱在心脏移植受者中的临床应用。

供体来源的无细胞dna （dd-cfDNA）和外周基因表达谱（pGEP）是监测心脏移植（HT）受者排斥反应的工具。我们的目的是评估dd-cfDNA/pGEP在HT受体中的联合应用。方法：我们使用配对dd-cfDNA(AlloSure-AS)/GEP（AlloMap-AM）结果（HeartCare-CareDx-CA-USA）对2019年至2023年间的HT受体进行评估。排除多器官移植受者。通过心内膜心肌活检对样本进行评估。移植后5个月内GEP评分为bbb30，移植后5个月内为34；dd-cfDNA阳性≥0.12%。根据dd-cfDNA/GEP结果将样品分为四组。结果：2388例（257例）患者中，（-）dd-cfDNA/(-)GEP 1437例（60.2%），（-）dd-cfDNA/(+)GEP 419例（17.5%），（+）dd-cfDNA/(-)GEP 375例（15.7%），（+）dd-cfDNA/(+)GEP 157例（6.6%）。中位年龄为55岁，27%为女性。从HT到样本的中位时间为10个月[IQR 5-18]。中位AS阳性水平为0.22% [IQR 0.15-0.48]。29%的样本具有相关的EMB结果，主要在（+）dd-cfDNA/(+)GEP组（55%），其次是不一致组（+）dd-cfDNA/(-)GEP（49%）和（-）dd-cfDNA/(+)GEP（32%）和（-）dd-cfDNA/(-)GEP组（20%,p < 0.001）。排斥反应发生率为7.1%，以（+）dd-cfDNA/(+)GEP组最高（15.1%），其次是（+）dd-cfDNA/(-)GEP组（10.9%）、（-）dd-cfDNA/(-)GEP组（3.8%）和（-）dd-cfDNA/(+)GEP组（3.7%）（p < 0.001）。中位随访时间为29个月[IQR 16-42]。与（-）dd-cfDNA/(-)GEP组相比，（+）dd-cfDNA/(+)GEP组的死亡风险增加（HR: 6.1, 95% CI [2.5-14.8]; p < 0.001）。同样，（+）dd-cfDNA/(-)GEP组显示出几乎6倍的死亡率（HR: 5.6, 95% CI [1.8-17.5]; p = 0.003）。结论：（+）dd-cfDNA/(+)GEP患者活检频率更高，排异率更高。与阴性协和组相比，在dd-cfDNA阈值分别为0.12%和0.20%时，该组的死亡风险增加了6倍，死亡风险增加了7倍。

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来源期刊

Clinical Transplantation 医学-外科

CiteScore

3.70

自引率

4.80%

发文量

286

审稿时长

2 months

期刊介绍： Clinical Transplantation: The Journal of Clinical and Translational Research aims to serve as a channel of rapid communication for all those involved in the care of patients who require, or have had, organ or tissue transplants, including: kidney, intestine, liver, pancreas, islets, heart, heart valves, lung, bone marrow, cornea, skin, bone, and cartilage, viable or stored. Published monthly, Clinical Transplantation’s scope is focused on the complete spectrum of present transplant therapies, as well as also those that are experimental or may become possible in future. Topics include: Immunology and immunosuppression; Patient preparation; Social, ethical, and psychological issues; Complications, short- and long-term results; Artificial organs; Donation and preservation of organ and tissue; Translational studies; Advances in tissue typing; Updates on transplant pathology;. Clinical and translational studies are particularly welcome, as well as focused reviews. Full-length papers and short communications are invited. Clinical reviews are encouraged, as well as seminal papers in basic science which might lead to immediate clinical application. Prominence is regularly given to the results of cooperative surveys conducted by the organ and tissue transplant registries. Clinical Transplantation: The Journal of Clinical and Translational Research is essential reading for clinicians and researchers in the diverse field of transplantation: surgeons; clinical immunologists; cryobiologists; hematologists; gastroenterologists; hepatologists; pulmonologists; nephrologists; cardiologists; and endocrinologists. It will also be of interest to sociologists, psychologists, research workers, and to all health professionals whose combined efforts will improve the prognosis of transplant recipients.