Klotho: Therapeutic Agent for Ischemia Reperfusion Induced Acute Kidney Injury

Klotho：缺血再灌注引起的急性肾损伤的治疗剂

• 批准号: 8963337
• 负责人: Ming-Chang Hu
• 金额: $ 12.11万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8963337
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Adult; Biological Markers; Cardiac; Cardiac Surgery procedures; Chronic; Chronic Kidney Failure; Clinical; Clinical Investigator; Clinical Trials; Collaborations; Coronary Artery Bypass; Creatinine; Data; Development; Diagnostic; Disease; End stage renal failure; Exposure to; Foundations; Frequencies; Future; Genomics; Human; Intervention; Ischemia; Kidney; Measures; Mission; Modeling; Morbidity - disease rate; Nephrotoxic; Nested Case-Control Study; Operative Surgical Procedures; Outcome; Patients; Perioperative; Pharmaceutical Preparations; Recombinants; Recovery; Reperfusion Injury; Reperfusion Therapy; Risk; Rodent; Sampling; Seeds; Serum; Severities; Staging; Testing; Therapeutic; Therapeutic Agents; Therapeutic Clinical Trial; Time; Translational Research; Translations; Validation; Wit; Work; clinically significant; cohort; high risk; improved; intraperitoneal; klotho protein; mortality; novel; novel diagnostics; novel therapeutics; prevent; prognostic; prospective; public health relevance; response

 DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a serious condition with high morbidity and mortality and AKI patients are at high risk of developing chronic kidney disease (CKD) and end-stage renal disease. The poor outcome is mainly attributable to: (1) Lack of efficacious interventions to prevent or mitigate kidney damage after exposure to renal insults; and (2) Limited strategies to slow or stop progression to CKD after an episode of AKI. We are in dire need of novel diagnostic and therapeutic strategies for patients with AKI or at high risk of AKI. Klotho protein is highly expressed in the kidney. We have demonstrated that Klotho is drastically reduced in rodents with AKI induced by ischemia-reperfusion injury and nephrotoxic drug and Klotho is not a mere biomarker but Klotho deficiency is pathogenetically important. The rodent data supports three therapeutic windows with different objectives. 1. When given before or immediately after renal insult, recombinant Klotho prevents AKI. 2. When given immediately after exposure to IRI, Klotho promoted renal recovery. 3. When given one day after AKI continued for ~10 days, Klotho retarded AKI progression to CKD and improved cardiac remodeling. Hence, Klotho is a potential therapeutic agent post-AKI that can be of enormous clinical significance. To launch the clinical trial, the first step is to explore whether humans with AKI have Klotho deficiency which has been repeatedly confirmed in rodent AKI models. We hypothesize that humans with incident AKI post cardiac surgery have Klotho deficiency. To prove our hypothesis, we will examine serum Klotho levels prior and post cardiac surgery and define whether Klotho levels in serum decrease and the decline precedes an increase in serum creatinine in adults at risk of AKI who undergo cardiac surgery. We will further explore the association of lower serum Klotho levels with the episode and severity of AKI. This is the first translational step to investigate whether Klotho deficiency in rodents is reproduciblein humans with AKI. We will conduct a nested case-control study in two well-established cohorts: Translational Research Investigating Biomarker End-Points cohort, a completed multicenter prospective cohort and. Coronary Artery Bypass Graft Surgery Genomic Cohort, an ongoing multicenter prospective cohort. We will have banked sera of AKI patients and controls from the completed subjects from these two cohorts. Confirmation of our hypothesis will constitute a foundation for future early clinical trials in humans to validate Klotho as novel target of AKI wit diagnostic, prognostic, and therapeutic applications, which is one mission of PAR-14-006, i.e., target validation.

 描述（由申请方提供）：急性肾损伤（阿基）是一种发病率和死亡率较高的严重疾病，阿基患者发生慢性肾病（CKD）和终末期肾病的风险较高。不良结局主要归因于：（1）缺乏有效的干预措施来预防或减轻暴露于肾损伤后的肾损伤;和（2）阿基发作后减缓或阻止进展为CKD的策略有限。我们迫切需要针对阿基患者或阿基高风险患者的新型诊断和治疗策略。Klotho蛋白在肾脏中高度表达。我们已经证明，Klotho在患有由缺血-再灌注损伤和肾毒性药物诱导的阿基的啮齿动物中急剧减少，并且Klotho不仅仅是一种生物标志物，但Klotho缺乏症在病理学上是重要的。啮齿动物数据支持具有不同目标的三个治疗窗口。1.当在肾损伤之前或之后立即给予时，重组Klotho可预防阿基。2.当暴露于IRI后立即给药时，Klotho促进了肾脏恢复。3.在阿基持续约10天后的第1天给药时，Klotho可延缓阿基进展为CKD，并改善心脏重塑。因此，Klotho是一种潜在的AKI后治疗药物，具有巨大的临床意义。为了启动临床试验，第一步是探索患有阿基的人是否患有Klotho缺陷症，这在啮齿动物阿基模型中得到了反复证实。我们假设心脏手术后发生阿基的人患有Klotho缺乏症。为了证明我们的假设，我们将检查心脏手术前后的血清Klotho水平，并确定血清Klotho水平是否降低，以及在接受心脏手术的阿基风险成人中血清肌酐升高之前是否下降。我们将进一步探索较低的血清Klotho水平与阿基的发作和严重程度的相关性。这是研究啮齿类动物中Klotho缺乏症是否可在患有阿基的人类中重现的第一个翻译步骤。我们将在两个成熟的队列中进行嵌套病例对照研究：转化研究调查生物标志物终点队列，一个完整的多中心前瞻性队列和。冠状动脉旁路移植术基因组队列，一项正在进行的多中心前瞻性队列研究。我们将储存来自这两个队列的已完成受试者的阿基患者和对照血清。我们的假设的证实将构成未来人类早期临床试验的基础，以验证Klotho作为阿基的新靶标，具有诊断、预后和治疗应用，这是PAR-14-006的使命之一，即，目标验证