MIDAS: MIcroangiopathy, endothelial Damage in Adults undergoing Stem cell transplantation

MIDAS：接受干细胞移植的成人的微血管病、内皮损伤

• 批准号: 10482388
• 负责人: Sumithira Vasu
• 金额: $ 74.31万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-20 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10482388
• 关键词: Acute Graft Versus Host Disease; Address; Adult; Age; Allogenic; Annual Reports; Area; Biological; Biological Markers; Blood; Caring; Cell Therapy; Cells; Child; Clinical; Clinical Data; Clinical Markers; Clinical Research; Cohort Studies; Complement; Complement Activation; Complication; Consensus; Data; Development; Diagnosis; Diagnostic; Early Diagnosis; Elderly; Endothelium; Enrollment; Etiology; Event; Financial cost; Flare; Frequencies; Functional disorder; Future; Health; Hematopoietic Stem Cell Transplantation; Hemolytic Anemia; Hospitalization; Immunosuppression; Incidence; Individual; Infection; Injury; Institution; Intensive Care Units; Interferons; Interruption; Intervention; Knowledge; Length; Life; Measures; Monitor; Mononuclear; Neurologic Symptoms; Ohio; Organ; Outcome; Pathogenesis; Patient risk; Pediatric cohort; Persons; Phenotype; Plasma; Population; Predisposition; Prevention; Procedures; Prospective Studies; Prospective cohort; Publications; Publishing; Rehabilitation therapy; Renal function; Reporting; Resolution; Risk Factors; Role; Sampling; Series; Stem cell transplant; Testing; Therapeutic; Time; Toxic effect; Transplant Recipients; Transplantation; Universities; Work; base; cell growth; chemotherapy; clinical database; clinical diagnosis; clinical phenotype; clinical risk; cohort; conditioning; diagnostic strategy; evidence based guidelines; graft vs host disease; hematopoietic cell transplantation; high risk; improved; indexing; individual patient; inhibitor; interest; kidney dysfunction; mortality; new therapeutic target; novel therapeutic intervention; older patient; organ injury; post-transplant; prospective; research study; routine screening; screening; screening guidelines; therapeutic target; thrombotic; transplant centers

MIDAS: Microangiopathy, endothelial Damage in Adults undergoing Stem cell transplantation ABSTRACT Hematopoietic cell transplant-associated thrombotic microangiopathy (HCT-TMA) is a clinical diagnosis based on consensus criteria and associated with high mortality rates (80%). Approximately 9,000 hematopoietic cell transplant (HCT) procedures are performed in the U.S. annually, and reported frequencies of HCT-TMA are highly variable due to lack of routine screening. HCT-TMA is a morbid and potentially life-threatening complication of HCT including microangiopathic hemolytic anemia, renal dysfunction and neurological symptoms. The initiating event of HCT-TMA appears to be endothelial injury, and extensive data indicate decline in endothelial health as people age suggesting that HCT-TMA might be more frequent or severe in older persons. Preliminary data indicate a bimodal distribution of HCT-TMA in adults, with a peak early after transplantation, which is well described in children, but a second later peak 3-6 months after transplant, sometimes associated with a flare of graft versus host disease (GVHD) during taper of immune suppression. There is no reported prospective study of HCT-TMA in adults thus risk factors and outcomes are currently unknown. This is a key gap in current knowledge and we plan to address this gap in our proposal. The need for a prospective adult cohort study of HCT-TMA is urgent as older patients are increasingly eligible for HCT. This study will define clinical phenotypes, risk factors, and possible therapeutic strategies for HCT-TMA. Our overarching hypothesis is that “The etiology and risk factors for HCT-TMA are different in adults than children, and that these differences importantly modify potential diagnostic and therapeutic strategies”. We propose to identify strategies that will define HCT recipients with increased susceptibility to HCT-TMA occurring early after transplantation, and later after establishment of GVHD. Identifying endothelial injury occurring post-HCT at the earliest possible time will allow for prompt clinical intervention and interruption of the cycle of endothelial injury and complement activation. The centers participating in this study are ideal for this work because they are large transplant centers with a strong track record of successful clinical research and study enrollment with a long-standing interest in HCT- TMA, evidenced by previous publications in the area. We will use our prospectively generated, well-annotated clinical database to test hypotheses regarding pathophysiology, for example, that GVHD is a major contributor to HCT-TMA by examining clinical risk factors and biomarkers of endothelial injury. We will measure the financial cost of HCT-TMA, late organ toxicity and will formulate and test a predictive index for HCT-TMA to target monitoring and treatment to highest-risk individuals. In summary, this study will provide essential data to identify persons at highest risk of HCT-TMA to allow testing of future clinical interventions such as studies of endothelial protecting agents and complement or interferon inhibitors for HCT-TMA and development of evidence-based guidelines for screening and diagnosis of HCT-TMA in adults.

MIDAS：接受干细胞移植的成人中的微血管病和内皮损伤 摘要 造血细胞移植相关血栓性微血管病（HCT-TMA）是一种临床诊断基础， 与高死亡率（80%）相关。大约9,000个造血细胞 在美国，每年进行一次造血干细胞移植（HCT）程序，HCT-TMA的报告频率为 由于缺乏常规筛查而高度可变。HCT-TMA是一种病态的，可能危及生命的疾病。 HCT并发症包括微血管病性溶血性贫血、肾功能不全和神经系统疾病 症状HCT-TMA的起始事件似乎是内皮损伤，大量数据表明， 提示HCT-TMA在老年人中可能更频繁或更严重。 初步数据表明HCT-TMA在成人中呈双峰分布，在移植后早期达到峰值， 这在儿童中有很好的描述，但在移植后3-6个月出现第二个高峰，有时与移植有关。 在逐渐减少免疫抑制期间出现移植物抗宿主病（GVHD）。未报告 在成人中进行的HCT-TMA前瞻性研究，因此风险因素和结局目前尚不清楚。这是一个关键的差距 我们计划在我们的提案中解决这一差距。对前瞻性成人队列的需求 随着越来越多的老年患者符合HCT的条件，HCT-TMA的研究迫在眉睫。本研究将定义临床 HCT-TMA的表型、风险因素和可能的治疗策略。我们的首要假设是 “HCT-TMA的病因和危险因素在成人中与儿童不同，这些差异 重要地改变了潜在诊断和治疗策略”。我们建议确定战略， 定义HCT受体在移植后早期对HCT-TMA的易感性增加， GVHD建立后。尽早识别HCT后发生的内皮损伤， 允许及时的临床干预和中断内皮损伤和补体激活的循环。 参与这项研究的中心是这项工作的理想选择，因为它们是大型移植中心， 成功的临床研究和研究招募的良好记录，对HCT有着长期的兴趣- TMA，该地区以前的出版物证明。我们将使用我们的前瞻性生成的，注释良好的 临床数据库，以测试关于病理生理学的假设，例如，GVHD是一个主要的贡献者， HCT-TMA通过检查临床危险因素和内皮损伤的生物标志物。我们将衡量金融 HCT-TMA的成本，晚期器官毒性，并将制定和测试HCT-TMA的预测指数，以靶向 对最高风险个体进行监测和治疗。总之，这项研究将提供必要的数据，以确定 HCT-TMA风险最高的人，允许测试未来的临床干预措施，如内皮细胞研究 HCT-TMA的保护剂和补体或干扰素抑制剂以及循证医学的发展 成人HCT-TMA筛查和诊断指南。