Mechanisms of Cell-Free Plasma Hemoglobin-Mediated Renal Injury after Cardiopulmonary Bypass

体外循环后无细胞血浆血红蛋白介导的肾损伤机制

• 批准号: 10654592
• 负责人: Nahmah Kim-Campbell
• 金额: $ 15.92万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10654592
• 关键词: Acids; Acute Renal Failure with Renal Papillary Necrosis; Affect; Age; Antioxidants; Apoptotic; Biochemical; Biological Availability; Biological Markers; Biology; Cardiac Surgery procedures; Cardiopulmonary Bypass; Cell Death; Cells; Child; Childhood; Childhood Injury; Clinical; Clinical Research; Consumption; Creatinine; Critically ill children; Cytoplasm; Data; Disease; Electron Spin Resonance Spectroscopy; Environment; Epithelial Cells; Erythrocytes; Experimental Models; Exposure to; Female; Foundations; Free Radicals; Functional disorder; Future; Gender; Glutathione; Guidelines; Haptoglobins; Heart Diseases; Hemeproteins; Hemoglobin; Hemoglobin concentration result; Hemolysis; Histologic; Histology; Human; Hydrogen Peroxide; Infant; Inflammation; Injury; Injury to Kidney; Institution; International; Intervention; Iron; Ischemia; Kidney; Kidney Diseases; Knowledge; LCN2 gene; Length of Stay; Lipids; Malaria; Measurement; Measures; Mediating; Mentors; Methods; Modeling; Morbidity - disease rate; Nitric Oxide; Nitric Oxide Donors; Nitrites; Operative Surgical Procedures; Organ; Outcome; Oxidation-Reduction; Oxidative Stress; Patients; Peroxidases; Pharmaceutical Preparations; Plasma; Porphyrins; Production; Prussian blue; Rattus; Reducing Agents; Renal Blood Flow; Renal function; Reperfusion Therapy; Research; Research Design; Research Personnel; Resources; Risk Factors; Rodent; Rodent Model; Role; Sampling; Scientist; Sepsis; Serum; Sickle Cell Anemia; Stains; Superoxides; Supplementation; Testing; Toxic effect; Tubular formation; Urine; Venous; ascorbate; clinical translation; defined contribution; design; experience; experimental study; haptoglobin-hemoglobin complex; heme a; hypoperfusion; improved; in vivo; insight; interest; lipidomics; male; mortality; novel; organ injury; oxidation; oxidative damage; pediatric patients; prospective; renal artery; skills; therapeutic target; translational study

ABSTRACT Cardiopulmonary bypass (CPB) in pediatric cardiac surgery has been refined over the years, yet unfavorable outcomes such as acute kidney injury (AKI), which is associated with mortality and prolonged ICU and hospital length of stay, remains problematic and incompletely understood. Cell-free plasma hemoglobin (PHb) can be produced in large quantities during CPB and other forms of extracorporeal therapy. The ultimate focus of this proposal is to contribute to the knowledge of the pathophysiology and mechanisms of the role of PHb in post-CPB AKI in order to identify clinically meaningful therapies. The research plan for this proposal was designed to examine this in a prospective clinical study while also attempting to have a more mechanistic approach to defining potential therapeutic targets using an in vivo rodent model of extracorporeal therapy. Preliminary data demonstrated the association of PHb with AKI in children undergoing CPB with age and gender-related differences and is associated with decreased nitric oxide (NO) bioavailability and increased indicators of oxidative stress. Recent preliminary data also shows that end products of lipid oxidation (9 and 13-hydroxyoctadecadienoic acid [HODEs]) can be bioactive and lead to increased requirements for vasoactive medications. This proposal focuses on the idea that PHb and PHb-haptoglobin complexes have peroxidase activity that consumes reductants or antioxidants such as ascorbate, glutathione, and nitric oxide (NO) and also leads to the production of HODEs. These biochemical indicators of oxidative stress will be measured in both human and rat samples. The bioactivity of the HODEs, changes in NO bioavailability, and depletion of antioxidants will lead to functional effects (evaluated by need for vasoactive medication, change in renal blood flow, and renal function) and histological evidence of renal injury. The use of a rodent model of extracorporeal therapy will allow invasive measurements of renal blood flow, in vivo NO availability, and ability to evaluate kidney histology. The introduction of targeted interventions in this experimental model, namely nitrite, a NO donor, and MnPP, which eliminates both superoxide and its dismutation product H2O2 (the fuel for peroxidase activity), is thus expected to ameliorate renal injury. This proposal will lead to a greater ability to identify risk factors of PHb-mediated renal injury after CPB and illuminate the mechanisms by which PHb drives AKI. Dr. Kim-Campbell has assembled a mentoring team of internationally recognized investigators led by Dr. Hülya Bayır, an expert in oxidative stress and free radical biology. The available resources, institutional support, and exceptional mentoring environment will provide Dr. Kim-Campbell with the foundation to become an independent clinician scientist with expertise in meaningful mechanistically-supported methods to improve adverse renal outcomes in extracorporeal therapies.

摘要 多年来，儿科心脏手术中的体外循环(Cpb)一直在改进，但 不良结局，如急性肾损伤(AKI)，这与死亡率和ICU时间延长有关 和住院时间，仍然是有问题的，而且还不完全了解。无细胞血浆血红蛋白 (PHB)可在体外循环和其他形式的体外治疗期间大量生产。终极的 这项建议的重点是促进对血管紧张素转换酶的病理生理学和作用机制的了解 PHB在CPB术后AKI中的应用，以确定临床上有意义的治疗方法。这项提案的研究计划 是为了在前瞻性的临床研究中检验这一点，同时也试图有一种更具机械性的 使用体外治疗的活体啮齿动物模型确定潜在治疗靶点的方法。 初步数据显示，在接受CPB的儿童中，PHB与AKI的关系与年龄和年龄有关 与性别相关的差异，并与一氧化氮(NO)生物利用度降低和增加有关 氧化应激指标。最近的初步数据还表明，脂质氧化的最终产物(9和 13-羟基十八碳二烯酸[HODES])可以具有生物活性，并导致对血管活性的需求增加 药物。这一建议集中在PHB和PHB-结合珠蛋白复合体具有过氧化物酶的观点 消耗还原剂或抗氧化剂的活动，如抗坏血酸、谷胱甘肽和一氧化氮(NO)以及 也导致了霍兹的生产。这些氧化应激的生化指标将在 人和老鼠的样本都有。HODE的生物活性，NO生物利用度的变化，以及 抗氧化剂将导致功能影响(通过血管活性药物的需要，肾脏血液的变化来评估 血流和肾功能)和肾脏损伤的组织学证据。一种体外啮齿动物模型的应用 治疗将允许对肾脏血流量进行有创性测量，体内无可用性，并有能力进行评估 肾脏组织学检查。在这个实验模型中引入了有针对性的干预措施，即亚硝酸盐，一种NO 供体，以及消除超氧化物及其歧化产物过氧化氢(过氧化物酶的燃料)的MnPP 活动)，因此有望减轻肾脏损伤。 这一建议将使识别CPB后PHB介导的肾损伤的危险因素的能力更强 并阐明了PHB驱动AKI的机制。金-坎贝尔博士组建了一个指导团队 由氧化应激和自由基专家Hülya Bayır博士领导的国际公认的调查人员 生物学。可用的资源、机构支持和特殊的指导环境将为Dr。 金-坎贝尔与基金会合作，成为一名独立的临床科学家，拥有有意义的专业知识 在体外治疗中改善不良肾脏结果的机械支持的方法。

项目成果

Therapeutic Plasma Exchange Is Associated With Improved Major Adverse Kidney Events in Children and Young Adults With Thrombocytopenia at the Time of Continuous Kidney Replacement Therapy Initiation.

• DOI: 10.1097/cce.0000000000000891
• 发表时间: 2023-04
• 期刊: Critical care explorations
• 作者: Fuhrman, Dana Y.;Thadani, Sameer;Hanson, Claire;Carcillo, Joseph A.;Kellum, John A.;Park, Hyun Jung;Lu, Liling;Kim-Campbell, Nahmah;Horvat, Christopher M.;Arikan, Ayse Akcan
• 通讯作者: Arikan, Ayse Akcan