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: 10033943
• 负责人: Sumithira Vasu
• 金额: $ 81.38万
• 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/10033943
• 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 Diagnosis; clinical database; clinical phenotype; clinical risk; cohort; conditioning; evidence based guidelines; graft vs host disease; hematopoietic cell transplantation; high risk; improved; indexing; individual patient; inhibitor/antagonist; 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; 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的微血管病变和内皮损伤 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 根据共识标准，并与高死亡率(80%)相关。大约9000个造血细胞 移植(HCT)手术每年在美国进行，据报道，HCT-TMA的频率为 由于缺乏常规筛查，变数很大。HCT-TMA是一种病态的、可能危及生命的疾病 HCT的并发症包括微血管病理性溶血性贫血、肾功能障碍和神经系统 症状。HCT-TMA的始发事件似乎是内皮损伤，广泛的数据表明下降 随着年龄的增长，血管内皮细胞的健康状况不佳，这表明HCT-TMA在老年人中可能更常见或更严重。 初步数据显示，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 随着移植物抗宿主病(GVHD)的爆发，免疫抑制逐渐减弱。目前尚无报道 成人HCT-TMA的前瞻性研究因此，危险因素和结果目前尚不清楚。这是一个关键的差距 在目前的知识中，我们计划在我们的提案中解决这一差距。对未来成人队列的需求 随着老年患者越来越有资格接受HCT，对HCT-TMA的研究迫在眉睫。这项研究将定义临床 HCT-TMA的表型、危险因素和可能的治疗策略。我们最重要的假设是 成人和儿童的HCT-TMA的病因和危险因素是不同的，这些差异 重要的是修改潜在的诊断和治疗策略“。我们建议确定以下战略： 确定移植后早期及以后发生的HCT-TMA易感性增加的HCT受者 在GVHD成立后。尽早确定HCT后发生的内皮损伤将 允许及时的临床干预和中断内皮细胞损伤和补体激活的循环。 参与这项研究的中心非常适合这项工作，因为它们是大型移植中心，有 成功的临床研究和研究登记的良好记录，并长期对HCT感兴趣- TMA，该地区以前的出版物证明了这一点。我们将使用预期生成的、注释良好的 临床数据库，以测试有关病理生理学的假设，例如，GVHD是主要贡献者 通过检测血管内皮细胞损伤的临床危险因素和生物标志物对HCT-TMA的影响。我们将衡量财务状况 HCT-TMA的成本，晚期器官毒性，并将制定和测试HCT-TMA靶向的预测指标 对高危人群进行监测和治疗。总之，这项研究将提供必要数据，以确定 HCT-TMA风险最高的人群允许测试未来的临床干预措施，如内皮研究 HCT-TMA保护剂、补体或干扰素抑制剂及循证研究进展 成人HCT-TMA筛查和诊断指南。