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: 8705009
• 负责人: Mats Hidestrand
• 金额: $ 62.11万
• 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/8705009
• 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18万美国人接受实体器官移植。每年有超过2000例心脏移植手术，其中包括超过300例儿科心脏移植手术，仅在美国就有超过2万名活体心脏移植受者。心脏移植后的一年生存率提高到90%以上；然而，10年生存率仍低于60%。随着手术和术后管理的改善，排斥反应已成为预后的主要决定因素。早期发现排斥反应有助于早期治疗，从而改善早期和晚期的功能和生存率。