AKI-Sapere- a novel prognostic of Acute Kidney Injury due to cardiac surgery

AKI-Sapere——心脏手术所致急性肾损伤的新型预后

• 批准号: 10001147
• 负责人: Natalia Mitin
• 金额: $ 89.32万
• 依托单位: SAPERE BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001147
• 关键词: 9p21; Acute Renal Failure with Renal Papillary Necrosis; Age; Aging; Biological Assay; Biological Markers; CDKN2A gene; Cardiac Surgery procedures; Cardiovascular Diseases; Cardiovascular Surgical Procedures; Cell Cycle; Cells; Characteristics; Chronic Kidney Failure; Chronology; Clinic; Clinical; Clinical Research; Clinical Trials; Coronary Artery Bypass; Creatinine; Critical Illness; Cytotoxic Chemotherapy; DNA Markers; Data Analyses; Devices; Diagnosis; Diagnostic; Diagnostic radiologic examination; Etiology; FDA approved; Genetic Predisposition to Disease; Healthcare; Image; Imaging Techniques; Individual; Injury to Kidney; Kidney; Kidney Failure; Life Experience; Logistic Regressions; Measurement; Measures; Medical Imaging; Modeling; Molecular; Morbidity - disease rate; Multi-Institutional Clinical Trial; Operative Surgical Procedures; Organ Transplantation; Outcome; Patient Care; Patient risk; Patients; Performance; Perioperative; Pharmacology; Phase; Pilot Projects; Predictive Value; Prevention; Prevention strategy; Procedures; Process; Prophylactic treatment; Protocols documentation; Recommendation; Regulator Genes; Renal dialysis; Renal function; Research; Risk; Risk Factors; Risk stratification; Sensitivity and Specificity; Serum; Sharps Injury; Site; Source; Supportive care; Surgical complication; Testing; Therapeutic; Tissues; Validation; Work; base; chemotherapy; clinical development; clinical practice; design; healthspan; high risk; improved; in vivo; innovation; kidney dysfunction; meetings; molecular marker; mortality; mutational status; novel; patient stratification; phase 1 study; phase 2 study; predictive modeling; prognostic; regenerative; renal damage; risk minimization; risk variant; senescence; surgical risk; tool; treatment strategy; trial design

ABSTRACT Acute kidney injury (AKI) is common, expensive to treat, and associated with >50% mortality. Each year, millions of patients undergo cardiovascular surgery, medical imaging, or cytotoxic chemotherapy, all of which place them at significant risk for AKI. Around 30% of cardiac surgery patients develop AKI, with even mild AKI significantly increasing the risk of negative outcomes such as progression to chronic kidney disease and 30-day mortality. Although recent research on renal biomarkers has shown promise in diagnosing AKI progression, as yet no tests or models can effectively identify prior to surgery patients at risk for AKI initiation. If patients at risk for developing AKI can be accurately identified before surgery, preoperative and perioperative procedures could be modified to minimize the risk of AKI. Such risk minimization is particularly important since there are no pharmacologic therapies available for the effective prevention or treatment of AKI. Therefore, a clinical tool to predict AKI prior to its initiation remains a critical unmet need. Only through early prediction can clinicians make informed decisions to improve the care of patients at risk of AKI and to limit the burden of this catastrophic complication of surgery and critical illness. By utilizing our novel and robust assay for measuring a patient’s “molecular age”, HealthSpan Dx has developed AKI-Sapere, a multivariate assay that can successfully identify patients at risk for AKI initiation prior to coronary artery bypass graft (CABG) surgery. AKI-Sapere combines measurement of our innovative marker of molecular age along with a DNA marker of genetic predisposition for cardiovascular disease, and a baseline measurement of renal function. In a pilot study of 96 patients undergoing CABG procedures, AKI-Sapere predicted risk of AKI and was superior to AKI risk models composed of clinical variables, such as the Cleveland Clinic Thakar score, or a panel of ten renal biomarkers known to predict AKI progression. In this Fast Track proposal, we propose to conduct multi-center clinical trials to refine the risk score and validate the clinical utility of AKI-Sapere to identify patients at risk for AKI prior to CABG. Completion of these aims will demonstrate the clinical utility of AKI-Sapere in CABG patients and will allow us to bring this test to market, first as a lab developed test (LDT) and ultimately as an FDA-approved device. Prediction of AKI initiation by AKI- Sapere has the potential to dramatically change clinical practice by providing a significantly greater opportunity to intervene, to alter the ensuing renal insult, to council patients and clinicians, and to ultimately diminish the impact of AKI and the associated morbidity on patients and healthcare. Furthermore, use of AKI-Sapere for patient stratification in multiple settings would catalyze the clinical development of novel preventative and treatment strategies for AKI, including potentially AKI caused by sources other than CABG (high-risk surgery, organ transplantation, radiographic imaging and chemotherapy).

摘要 急性肾损伤(AKI)很常见，治疗费用昂贵，并与50%的死亡率相关。每年，数以百万计的 的患者接受心血管手术、医学成像或细胞毒性化疗，所有这些都使他们 对AKI来说风险很大。大约30%的心脏手术患者发生AKI，即使是轻微的AKI也明显 增加负面结果的风险，如进展为慢性肾脏疾病和30天死亡。 虽然最近对肾脏生物标记物的研究在诊断AKI进展方面显示出了希望，但到目前为止还没有 测试或模型可以有效地在手术前识别有启动AKI风险的患者。如果有风险的患者 发生AKI可以在手术前准确识别，术前和围手术期的操作可以 经过修改，将AKI的风险降至最低。这种风险最小化尤其重要，因为没有 可用于有效预防或治疗AKI的药物疗法。 因此，在AKI开始前预测其临床工具仍然是一个关键的未满足的需求。只通过早期 通过预测，临床医生可以做出明智的决定，以改善对有AKI风险的患者的护理，并限制 这一灾难性的手术并发症和危重疾病的负担。通过利用我们新颖而强大的检测方法 HealthSpan Dx公司开发了AKI-Sapere，这是一种多变量分析方法，用于测量患者的“分子年龄” 可以在冠状动脉旁路移植术(CABG)前成功识别启动AKI的风险患者 做手术。Aki-Sapere结合了对我们创新的分子年龄标记的测量以及DNA 心血管疾病遗传易感性的标志，以及肾功能的基线测量。在一个 对96名接受冠状动脉搭桥术的患者进行的试点研究，AKI-Sapere预测了AKI和AS的风险 优于由临床变量组成的AKI风险模型，如克利夫兰诊所的Thakar评分， 或者是一个由10个肾脏生物标志物组成的小组，这些标志物可以预测AKI的进展。 在这个快速通道提案中，我们建议进行多中心临床试验，以完善风险评分并验证 AKI-Sapere在冠脉搭桥术前识别AKI高危患者的临床应用。完成这些目标将 展示AKI-Sapere在CABG患者中的临床效用，并将使我们能够首先将这一测试推向市场 作为实验室开发的测试(LDT)，并最终作为FDA批准的设备。AKI引发AKI的预测 Sapere有可能通过提供显著更大的机会来极大地改变临床实践 进行干预，改变随之而来的肾脏损害，咨询患者和临床医生，并最终减少 AKI及其相关发病率对患者和医疗保健的影响。此外，使用AKI-Sapere进行 多个环境中的患者分层将催化新的预防和治疗的临床发展 急性心肌梗死的治疗策略，包括可能由冠脉搭桥术以外的来源引起的急性心肌梗死(高风险手术， 器官移植、放射成像和化疗)。