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

心脏手术相关的急性肾损伤（CSA-AKI）是一个主要的公共卫生负担。仅在美国，每年就有超过50万例心脏手术，其中多达64%的手术并发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。没有药物治疗可以可靠地预防或治疗CSA-AKI。基于动物模型和人类研究的强大病理生理学原理，我们提出铁调素和其他血红素/铁调节蛋白在CSA-AKI中起关键作用。 在目标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型前瞻性队列研究。CABG Genomics收集了详细的临床数据和生物标本，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2，000名患者术前测量血浆hepcidin，以测试其与CSA-AKI的相关性。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。我们将使用来自TRIBE-AKI研究的样本对我们的研究结果进行外部验证，该研究招募了1219名在北美6个研究中心接受心脏手术的高风险成人。在目标2中，我们将在巢式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，以测试这些标志物的早期变化是否与CSA-AKI独立相关。 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人患者。我们将在术前和术后分离外周血单核细胞，以研究单核细胞表达膜铁转运蛋白和其他血红素/铁调节蛋白之间的关系，通过流式细胞术检测，与CSA-AKI。我们还将评估术后早期单核细胞膜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。 在CSA-AKI背景下研究铁调素-铁转运蛋白-铁轴和其他血红素/铁调节蛋白可能对未来预防CSA-AKI的试验设计具有可操作的意义。与以前在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。这一建议将有助于确定针对铁稳态紊乱的治疗策略，具有最高的成功可能性。如果低术前hepcidin被证实为CSA-AKI的独立风险因素，则目前正在开发的hepcidin激动剂的预防性给药可以在未来的CSA-AKI预防研究中进行测试。或者，如果拟议的研究显示其他血红素/铁调节蛋白（例如，结合珠蛋白、CD 163、HO-1）对CSA-AKI的影响大于铁调素/膜铁转运蛋白，因此可以测试靶向这些蛋白质的治疗策略。

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.