Extracorporeal SuPAR Extraction to Prevent COVID-19-associated Acute Kidney Injury

体外 SuPAR 提取预防 COVID-19 相关的急性肾损伤

• 批准号: 10362860
• 负责人: Salim Hayek
• 金额: $ 32.67万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10362860
• 关键词: 2019-nCoV; Acute Renal Failure with Renal Papillary Necrosis; Address; Adult; Affect; Aftercare; Age; Antibodies; Binding; Biological Markers; Blood; Blood Circulation; Blood Component Removal; Bone Marrow Ablation; COVID-19 patient; Cells; Characteristics; Chronic Kidney Failure; Clinical; Clinical Trials; Complex; Creatinine; Critical Illness; Data; Diabetes Mellitus; Dialysis procedure; Disease; Effectiveness; Experimental Models; Functional disorder; Funding Opportunities; Generations; Goals; Guanosine Triphosphate Phosphohydrolases; Hospital Mortality; Hospitalization; Human; Hypertension; Hypovolemia; Immune; Immune Targeting; Immune system; Immunologic Receptors; Incidence; Infection; Inflammation; Injury to Kidney; Integrin alphaVbeta3; Interleukin-6; Interruption; Intravenous; Intrinsic factor; Kidney; Kidney Diseases; Kinetics; LCN2 gene; Length; Link; Lymphocyte; Measures; Mechanical ventilation; Mediator of activation protein; Membrane; Methods; Mitochondria; Monoclonal Antibodies; Monomeric GTP-Binding Proteins; Morbidity - disease rate; Outcome; Pathogenesis; Pathologic; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Placebos; Plasmapheresis; Prevention; Proteins; Proteinuria; RNA Viruses; Randomized; Randomized Clinical Trials; Reactive Oxygen Species; Renal function; Respiration; Respiratory Failure; Risk; Role; Safety; Serious Adverse Event; Severities; Signal Transduction; Signaling Protein; Stimulus; Symptoms; Testing; Treatment Efficacy; Tubular formation; Urine; Urokinase Plasminogen Activator Receptor; Virulence Factors; Virus; Work; arm; comorbidity; coronavirus disease; cytokine; health care service utilization; hemodynamics; inclusion criteria; inflammatory marker; innovation; insulin-like growth factor binding protein-related protein 1; kidney dysfunction; meetings; minimal risk; monocyte; mortality; nephrotoxicity; podocyte; prevent; primary endpoint; primary outcome; procalcitonin; randomized trial; response; secondary outcome; small molecule inhibitor; therapeutic target; treatment duration

Abstract Acute kidney injury (AKI) is a global problem that affects one in five hospitalized adults worldwide. It has a major impact on morbidity and healthcare utilization, with small changes in kidney function shown to be associated with both short and long-term complications. AKI is a characteristic feature of the disease caused by the SARS-CoV-2 virus, coronavirus disease 19 (COVID-19), with close to 50% of hospitalized patients developing acute kidney injury (AKI) and 20% of patients requiring dialysis. The pathophysiology of AKI is complex and dependent on both intrinsic factors (age, co-morbid diabetes, hypertension, pre-existing kidney disease) and extrinsic factors (nephrotoxic drugs, hypovolemia, intra-arterial contrast, infections). Inflammation is an under-explored but crucial link between intrinsic and extrinsic factors in the pathogenesis of AKI. We have identified soluble urokinase plasminogen activator receptor (suPAR) as an immune-derived mediator of kidney injury. The expression of suPAR by immune cells is heavily induced by various stimuli, notably RNA viruses such as SARS-CoV-2. High levels of suPAR in circulation are strongly predictive of kidney dysfunction, with prolonged exposure directly affecting the kidneys by pathologic activation of αvβ3 integrins expressed on podocytes, resulting in activation of GTPase, podocyte effacement and subsequent proteinuria. We have recently shown high suPAR levels predisposes patients to AKI in various clinical scenarios including the critically ill, likely by modulating mitochondrial respiration and inducing reactive oxygen species generation in proximal tubular cells, sensitizing them to additional insults. Most importantly, effects of suPAR on the kidneys were abrogated using anti-suPAR in experimental models, suggesting suPAR is a promising therapeutic target to mitigate AKI. We have found that suPAR is dramatically elevated in COVID-19 and independently predictive of AKI. Despite the significant burden of AKI overall and specifically in COVID-19, there has been little progress in the prevention and treatment of AKI. We hypothesize that suPAR extraction early in the hospitalization of patients with COVID-19 may decrease the risk of moderate to severe AKI. To that end we have planned a phase 1 clinical trial randomizing adult patients hospitalized for COVID-19 who have high suPAR levels to daily extracorporeal extraction of suPAR by apheresis using a suPAR-specific adsorber, or sham treatment for a total of 5 days. The primary outcome of the trial is the occurrence of treatment-related serious adverse events. Exploratory outcomes include the incidence of AKI, respiratory failure, and in-hospital mortality. We will assess the kinetics of suPAR extraction by measuring daily levels prior to and post-treatment, in addition to its impact on markers of inflammation and kidney function. The proposed work is innovative in that it is the first trial targeting an immune-derived factor for preventing kidney injury. In addition to advancing our understanding of the immune system as a mediator of kidney injury, this trial will clarify suPAR’s role as a pathogenic factor, with major implications for the treatment of kidney disease beyond COVID-19.

摘要 急性肾损伤（阿基）是一个全球性问题，影响全球五分之一的住院成人。它有一个 对发病率和医疗保健利用产生重大影响，肾功能发生微小变化 与短期和长期并发症有关。阿基是一种典型的疾病特征， 由SARS-CoV-2病毒，冠状病毒病19（COVID-19），近50%的住院患者 发生急性肾损伤（阿基），20%的患者需要透析。阿基的病理生理学是 复杂且依赖于两种内在因素（年龄、合并糖尿病、高血压、既存肾脏 疾病）和外在因素（肾毒性药物、血容量不足、动脉内造影剂、感染）。炎症 是阿基发病机制中内在和外在因素之间的一个未充分探索但至关重要的联系。我们有 确定可溶性尿激酶纤溶酶原激活物受体（suPAR）作为肾脏免疫源性介质 损伤suPAR在免疫细胞中的表达受各种刺激物的强烈诱导，特别是RNA病毒 例如SARS-CoV-2。循环中高水平的suPAR强烈预测肾功能不全， 长期暴露直接影响肾脏的病理激活αvβ3整合素表达， 足细胞，导致GT β活化，足细胞消失和随后的蛋白尿。我们有 最近显示，在各种临床情况下，高suPAR水平使患者易患阿基，包括 危重病，可能是通过调节线粒体呼吸和诱导活性氧产生， 近端肾小管细胞，使它们对额外的损伤敏感。最重要的是，suPAR对肾脏的影响 在实验模型中使用抗suPAR可以消除，这表明suPAR是一个有前途的治疗靶点 减轻阿基。我们已经发现suPAR在COVID-19中显著升高，并且独立预测 关于阿基尽管阿基的总体负担很大，特别是在COVID-19中， 阿基的预防和治疗进展。我们假设，suPAR提取早在 COVID-19患者住院治疗可能会降低中度至重度阿基的风险。为此我们 计划进行一项1期临床试验，随机选择因COVID-19住院的成年患者， 通过使用suPAR特异性吸附器进行单采血液成分术，每日体外提取suPAR的suPAR水平，或 假处理总共5天。试验的主要结局是治疗相关的 严重不良事件。探索性结局包括阿基、呼吸衰竭和住院期间的发生率 mortality.我们将通过测量治疗前和治疗后的每日水平来评估suPAR提取的动力学， 除了对炎症标志物和肾功能的影响外。这项工作具有创新性， 这是第一个针对免疫衍生因子预防肾损伤的试验。除了推进 我们对免疫系统作为肾损伤介质的理解，这项试验将阐明suPAR作为一种免疫调节剂的作用。 致病因子，对COVID-19之后的肾脏疾病治疗具有重大意义。