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（阿基）是常见的，治疗昂贵，并且与>50%的死亡率相关。每年都有数百万 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 阿基的风险很大。大约30%的心脏手术患者会发生阿基，即使是轻度阿基， 增加了负面结果的风险，如进展为慢性肾脏疾病和30天死亡率。 尽管最近对肾脏生物标志物的研究显示出诊断阿基进展的希望，但目前还没有 测试或模型可以在手术前有效地识别处于阿基开始风险中的患者。如果患者有 发生阿基可以在手术前准确识别，术前和围手术期操作可以 修改以最小化阿基的风险。这种风险最小化特别重要，因为 可用于有效预防或治疗阿基的药物疗法。 因此，在AKI开始之前预测阿基的临床工具仍然是一个关键的未满足的需求。只有通过早期 预测可以使临床医生做出明智的决定，以改善对有阿基风险的患者的护理， 这种灾难性的手术并发症和危重病的负担。通过利用我们的新的和强大的测定， 为了测量患者的“分子年龄”，HealthSpan Dx开发了AKI-Sapere，这是一种多变量分析， 可以成功识别冠状动脉旁路移植术（CABG）前有阿基启动风险的患者 手术AKI-Sapere将我们创新的分子年龄标记物沿着的测量与DNA 心血管疾病遗传易感性的标志物和肾功能的基线测量。中 对96例接受CABG手术的患者进行的初步研究，AKI-Sapere预测了阿基的风险， 优于由临床变量（例如克利夫兰诊所Thakar评分）组成的阿基风险模型的上级模型， 或已知预测阿基进展的一组十种肾脏生物标志物。 在这个快速通道提案中，我们建议进行多中心临床试验，以细化风险评分并验证 AKI-Sapere在CABG前识别阿基风险患者的临床效用。实现这些目标将 证明AKI-Sapere在CABG患者中的临床实用性，并将使我们能够首先将该测试推向市场 作为实验室开发的测试（LDT），并最终作为FDA批准的设备。通过阿基预测阿基启动- Sapere通过提供更大的机会，有可能极大地改变临床实践 干预，改变随后的肾损伤，理事会患者和临床医生，并最终减少 阿基和相关发病率对患者和医疗保健的影响。此外，使用AKI-Sapere用于 在多种情况下的患者分层将促进新型预防性和 阿基的治疗策略，包括可能由CABG以外的来源引起的阿基（高风险手术， 器官移植、放射成像和化学疗法）。