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

基本信息

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
项目类别：
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

项目摘要

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.

心脏手术相关的急性肾损伤（CSA-AKI）是一个重大的公共卫生负担。仅在美国每年就进行超过 500,000 例心脏手术，其中多达 64% 并发 CSA-AKI。发生 CSA-AKI 的患者的急性死亡率比未发生 CSA-AKI 的患者高 6 至 18 倍。没有药物疗法能够可靠地预防或治疗 CSA-AKI。基于动物模型和人体研究的强有力的病理生理学原理，我们提出铁调素和其他血红素/铁调节蛋白在 CSA-AKI 中发挥关键作用。在目标 1 和 2 中，我们将利用 CABG 基因组项目，这是一项针对接受心脏手术的成年患者的大型前瞻性队列研究。 CABG Genomics 收集了详细的临床数据和生物样本，包括术前和术后多个时间点的血浆/血清样本。在目标 1 中，我们将在术前测量 2,000 名患者的血浆铁调素，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，包括血浆 IL-6。我们将使用 TRIBE-AKI 研究的样本在外部验证我们的研究结果，该研究招募了 1219 名在北美 6 个地点接受心脏手术的高危成年人。在目标 2 中，我们将在嵌套 1:1 病例对照研究 (n=600) 中纵向测量血浆铁调素、游离血红蛋白、触珠蛋白、血红素结合蛋白、转铁蛋白饱和度和铁蛋白，以测试这些标记物的早期变化是否与CSA-AKI。在目标 3 中，我们将招募 250 名在波士顿三家主要医院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，以研究单核细胞铁转运蛋白和其他血红素/铁调节蛋白表达之间的关系，并通过流式细胞术和 CSA-AKI 进行检查。我们还将评估术后早期单核细胞铁转运蛋白和其他血红素/铁调节蛋白表达的变化是否与 CSA-AKI 相关。研究 CSA-AKI 背景下的铁调素-铁转运蛋白-铁轴和其他血红素/铁调节蛋白可能对设计未来预防 CSA-AKI 的试验具有可操作的意义。与之前在 CSA-AKI 中检查的许多其他标志物不同，这里提出的那些标志物直接参与 CSA-AKI 的发病机制并且是可靶向的。该提案将有助于确定针对铁稳态紊乱的最有可能成功的治疗策略。如果术前低铁调素被确认为 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开发的铁调素激动剂的预防性给药。或者，如果拟议的研究表明其他血红素/铁调节蛋白（例如触珠蛋白、CD163、HO-1）对 CSA-AKI 的影响比铁调素/铁转运蛋白更大，则可以测试针对这些蛋白的治疗策略。