Targeted, Highly Sensitive, Non-Invasive Cardiac Transplant Rejection Monitoring

有针对性、高灵敏度、无创的心脏移植排斥监测

• 批准号: 8562789
• 负责人: Mats Hidestrand
• 金额: $ 73.24万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-23 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8562789
• 关键词: Adult; Age; American; Biological Markers; Biopsy; Blinded; Cardiac; Catheters; Cells; Child; Childhood; Clinical; Complication; DNA; DNA Sequence; Data; Demographic Factors; Development; Early Diagnosis; Early treatment; Effectiveness; Frequencies; Gold; Graft Rejection; Heart Transplantation; Life; Methods; Modeling; Monitor; Organ; Organ Transplantation; Outcome; Pathologic; Pathology; Patients; Pilot Projects; Plasma; Postoperative Period; Risk; Sampling; Severities; Solid; Specificity; Testing; Transplant Recipients; Transplantation; Validation; allograft rejection; base; cost; cost effective; heart allograft; improved; innovation; novel; predictive modeling; prospective; public health relevance

DESCRIPTION (provided by applicant): Over 180,000 Americans are living with solid organ transplants. Each year over 2000 heart transplants, including over 300 pediatric heart transplants are performed resulting in over 20,000 living heart transplant recipients in the U.S. alone. One year survival following heart transplantation has improved to over 90%; however, 10 year survival remains less than 60%. With improvement in operative and postoperative management, rejection has become the major determinant of outcome. Earlier detection of rejection facilitates earlier treatment, which improves both early and late function and survival. The gold standard in surveillance of cardiac allograft rejection remains catheter based endomyocardial biopsy (EMB). To detect rejection early, surveillance biopsies must be performed at regular intervals; however, EMB is both expensive (over $4000) and invasive (major complications 1.9%). It is estimated that over 30,000 surveillance biopsies are performed each year identifying 3,000 rejections with over 300 major complications. There is a tremendous need for a highly sensitive, non-invasive method that reliably detects patients with rejection. This proposal will have high impact on the problem of rejection surveillance in cardiac transplantation promoting earlier detection, earlier treatment, and improved long term outcomes. Donor specific cf-DNA increases in patients with solid organ rejection. We have completed a blinded pilot study in 38 pediatric and adult heart transplant patients utilizing a novel, highly accurate, targeted sequencing approach which precisely quantifies the amount of donor specific cell free DNA (cf-DNA) and total cf-DNA in recipient plasma. This data established a threshold below which no sample had rejection (0/51), and above which all patients with ISHLT grade e2 rejection (6/6) were detected (100% sensitivity). We have assembled a consortium of 6 major pediatric and adult transplant centers for a blinded multi-center study with independent pathology and echo core labs to test this extremely promising, cost effective, and innovative approach. We will first determine a threshold and develop a predictive model and then validate both on a prospective and blinded sample set of 240 new pediatric and adult transplant recipients followed longitudinally for at least one full year. Finally we will explore the relationships between major pathologic and clinical observations and levels of donor specific and total cf-DNA. This method holds promise to enable the accurate and cost effective non- invasive determination of rejection in all solid organ transplantation.

描述（由申请人提供）：超过180，000名美国人生活在实体器官移植中。每年进行超过2000例心脏移植，包括超过300例儿科心脏移植，仅在美国就有超过20，000例心脏移植受者。心脏移植后的一年生存率已提高到90%以上;然而，10年生存率仍低于60%。随着手术和术后处理的改善，排斥反应已成为影响预后的主要因素。排斥反应的早期检测有助于早期治疗，从而改善早期和晚期功能以及生存率。 监测心脏移植排斥反应的金标准仍然是基于导管的肌内膜活检（EMB）。为了早期发现排斥反应，必须定期进行监测活检;然而，EMB既昂贵（超过4000美元）又有创（主要并发症1.9%）。据估计，每年进行超过30，000次监测活检，发现3，000例排斥反应，300多例严重并发症。非常需要一种高度敏感、非侵入性的方法，可以可靠地检测排斥反应患者。这一建议将对心脏移植中的排斥反应监测问题产生重大影响，促进早期检测、早期治疗和改善长期结局。 实体器官排斥患者中供体特异性cf-DNA增加我们在38名儿童和成人心脏移植患者中完成了一项盲法初步研究，采用了一种新型、高度准确的靶向测序方法，可精确定量受体血浆中供体特异性细胞游离DNA（cf-DNA）和总cf-DNA的量。该数据建立了一个阈值，低于该阈值，没有样品发生排斥反应（0/51），高于该阈值，检测到所有ISHLT e2级排斥反应的患者（6/6）（100%灵敏度）。我们已经组建了一个由6个主要的儿科和成人移植中心组成的联盟，进行了一项盲态多中心研究，并配备了独立的病理学和超声心动图核心实验室，以测试这种极具前景、成本效益和创新的方法。我们将首先确定一个阈值，并开发一个预测模型，然后在一个前瞻性和盲法样本集上进行验证，该样本集由240名新的儿科和成人移植受者组成，纵向随访至少一整年。最后，我们将探讨主要病理和临床观察结果与供体特异性和总cf-DNA水平之间的关系。该方法有望在所有实体器官移植中实现准确和成本有效的排斥反应的非侵入性测定。