Hepcidin-Ferroportin-Iron Axis in Cardiac Surgery-associated Acute Kidney Injury

心脏手术相关急性肾损伤中的铁调素-铁转运蛋白-铁轴

• 批准号: 10444522
• 负责人: David Evan Leaf
• 金额: $ 81.53万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444522
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Adult; Affect; Agonist; Animal Model; Attenuated; Blood Circulation; Boston; Cardiac; Cardiac Surgery procedures; Cardiac Volume; Cardiopulmonary Bypass; Case-Control Studies; Clinical Data; Clinical Trials; Complex; Critical Illness; Data; Development; Enrollment; Ferritin; Flow Cytometry; Future; Genomics; Haptoglobins; Heme; Heme Iron; Hemoglobin; Hemolysis; Hemopexin; Hepatocyte; Homeostasis; Hormones; Hospitals; Human; Immunology; Incidence; Inflammation; Infrastructure; Interleukin-6; Investigation; Iron; Iron Metabolism Disorders; Iron-Regulatory Proteins; Measures; Modeling; North America; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmacology; Plasma; Play; Postoperative Period; Prospective cohort study; Proteins; Public Health; Risk; Risk Factors; Role; SLC11A2 gene; Sampling; Site; Testing; Therapeutic; Time; Transferrin; Variant; animal data; base; biobank; cell type; design; experience; genetic regulatory protein; hepcidin; high risk; human data; injury prevention; innovation; metal transporting protein 1; monocyte; mortality; novel; oxidative damage; prevent; prophylactic; protein expression; research study; success; therapeutic target; uptake

Cardiac surgery-associated acute kidney injury (CSA-AKI) is a major public health burden. Over 500,000 cardiac surgeries are performed annually in the U.S. alone, with as many as 64% complicated by CSA-AKI. Those who develop CSA-AKI have a 6- to 18-fold higher acute mortality compared to those without CSA-AKI. No pharmacologic therapy reliably prevents or treats CSA-AKI. Based on a strong pathophysiologic rationale from both animal models and human studies, we propose that hepcidin and other heme/iron regulatory proteins play a key role in CSA-AKI. In Aims 1 and 2, we will leverage the CABG Genomics Project, a large prospective cohort study of adult patients who underwent cardiac surgery. CABG Genomics collected detailed clinical data and biospecimens, including plasma/serum samples pre- and postoperatively at multiple time points. In Aim 1, we will measure plasma hepcidin preoperatively in 2,000 patients to test its association with CSA-AKI. We will use multivariable models to adjust for potential confounders, including plasma IL-6. We will externally validate our findings using samples from the TRIBE-AKI study, which enrolled 1219 high-risk adults who underwent cardiac surgery at 6 sites in North America. In Aim 2, we will measure plasma hepcidin, free hemoglobin, haptoglobin, hemopexin, transferrin saturation, and ferritin longitudinally in a nested 1:1 case-control study (n=600) to test whether early changes in these markers are independently associated with CSA-AKI. In Aim 3, we will enroll 250 high-risk adult patients undergoing cardiac surgery at three major hospitals in Boston. We will isolate peripheral blood mononuclear cells pre- and postoperatively to investigate the relationship between monocyte expression of ferroportin and other heme/iron regulatory proteins, examined by flow cytometry, with CSA-AKI. We will also assess whether early postoperative changes in monocyte expression of ferroportin and other heme/iron regulatory proteins are associated with CSA-AKI. Investigating the hepcidin-ferroportin-iron axis and other heme/iron regulatory proteins in the setting of CSA-AKI could have actionable implications for the design of future trials to prevent CSA-AKI. Unlike many other markers previously examined in CSA-AKI, those proposed here are directly involved in the pathogenesis of CSA-AKI and are targetable. This proposal will help determine the therapeutic strategy targeting disordered iron homeostasis that has the highest likelihood of success. If low preoperative hepcidin is confirmed as an independent risk factor for CSA-AKI, prophylactic administration of hepcidin agonists, which are currently in development, could be tested in future studies of CSA-AKI prevention. Alternatively, if the proposed studies reveal that other heme/iron regulatory proteins (e.g., haptoglobin, CD163, HO-1) have a greater influence on CSA-AKI than hepcidin/ferroportin, therapeutic strategies targeting these proteins could be tested.

与心脏手术相关的急性肾脏损伤（CSA-AKI）是主要的公共卫生负担。仅在美国，每年一次进行超过500,000次心脏手术，CSA-AKI复杂多达64％。与没有CSA-AKI的人相比，那些开发CSA-AKI的人的急性死亡率高6至18倍。没有药理治疗可靠地阻止或治疗CSA-AKI。基于动物模型和人类研究的强大病理生理原理，我们建议肝素和其他血红素/铁调节蛋白在CSA-AKI中起关键作用。 在AIMS 1和2中，我们将利用CABG基因组学项目，这是一项针对接受心脏手术的成年患者的大量前瞻性队列研究。 CABG基因组学收集了详细的临床数据和生物测量，包括在多个时间点前后的血浆/血清样品。在AIM 1中，我们将在2,000名患者的术前测量血浆肝素，以测试其与CSA-AKI的关联。我们将使用多变量模型来调整潜在的混杂因素，包括等离子体IL-6。我们将使用Tribe-Aki研究的样本在外部验证我们的发现，该研究招募了1219名高危成年人，他们在北美6个地点进行了心脏手术。在AIM 2中，我们将在嵌套的1：1病例对照研究（n = 600）中测量血浆肝素，游离血红蛋白，触发蛋白，血红蛋白，转铁蛋白饱和度和铁蛋白，以测试这些标记的早期变化是否与CSA-AKAKI独立相关。 在AIM 3中，我们将在波士顿的三家主要医院接受250名接受心脏手术的高危成年患者。我们将在术前和术后分离外周血单核细胞，以研究甲状管素的单核细胞表达与其他血红素/铁调节蛋白，通过流式细胞仪与CSA-AKI检查。我们还将评估肾上腺素和其他血红素/铁调节蛋白的单核细胞表达的早期变化是否与CSA-AKI相关。 在CSA-AKI的环境中，研究肝素 - 铁蛋白铁轴和其他血红素/铁调节蛋白可能对预防CSA-AKI的未来试验具有可行的影响。与以前在CSA-AKI中检查的许多其他标记不同，此处提出的那些直接参与了CSA-AKI的发病机理，并且具有目标。该提案将有助于确定针对无效的铁稳态的治疗策略，该策略的成功可能性很高。如果将低术前肝动物确认为CSA-AKI的独立危险因素，则可以在未来的CSA-AKI预防研究中测试目前正在发育中的肝素激动剂的预防性肝癌。另外，如果拟议的研究表明，与肝素/铁蛋白蛋白相比，其他血红素/铁调节蛋白（例如Haptoglobin，CD163，HO-1）对CSA-AKI具有更大的影响，那么可以测试靶向这些蛋白质的治疗策略。