RENALASE IN ACUTE KIDNEY INJURY: UTILITY AS A BIOMARKER, AND THERAPEUTIC AGENT

描述（由申请人提供）：挑战领域（03-DK-102）是开发和验证新型无创方法，以在发生主要器官损伤和功能障碍之前的疾病早期阶段检测和监测与NIDDK相关的疾病。与目前难以在疾病过程中早期检测和/或需要侵入性程序（如组织或器官活检）的疾病相关的新诊断方法具有最高优先级。具体的挑战主题是开发早期，敏感，非侵入性的方法来诊断急性肾损伤。我们建议检查肾酶的效用，在我们的实验室发现的一种新分子，作为急性肾损伤的早期和敏感的生物标志物。急性肾损伤（阿基）是一种临床疾病，通常与败血症，手术和某些药物有关，影响高达20%的住院患者。流行病学数据表明，发生阿基的患者比未发生AKI的患者更有可能死亡，并且风险与肾损伤的严重程度以及伴随的肾功能下降成比例。阿基的有效治疗方案的开发受到以下事实的阻碍：诊断严重依赖于血清肌酐测量，因此通常在原始损伤后48-72小时进行。有一个明确和迫切的需要，以确定与阿基患者早期，最好的方法被认为是涉及识别生物标志物和他们的验证在人体临床试验。肾酶是一种胺氧化酶，可代谢多巴胺、肾上腺素和去甲肾上腺素等儿茶酚胺。它由肾近端小管合成，在血液中分泌，并在基础状态下持续经尿液排泄。肾酶水平可以通过蛋白质印迹或ELISA测量。初步数据表明，肾酶是阿基的一种新型生物标志物。中度严重缺血性损伤（全脑缺血45分钟），导致尿肾酶排泄的显著和持久的减少。这些数据非常令人兴奋，表明尿肾酶可能是缺血性阿基的早期生物标志物。本提案的主要目的是检验以下假设：尿肾酶可作为啮齿动物阿基的早期和敏感生物标志物，并且肾酶给药是治疗啮齿动物阿基的有用治疗选择。如果拟议的研究成功，未来的研究（不属于本提案的一部分）将旨在使用TRIBE-AKI数据库和/或类似的可用数据库验证肾酶作为人类阿基的生物标志物，并测试重组肾酶在人类阿基中的治疗效用。 公共卫生相关性：急性肾损伤（阿基）是一种通常与败血症、手术和某些药物相关的临床疾病，影响高达20%的住院患者，并与死亡率增加相关。阿基的有效治疗方案的开发受到以下事实的阻碍：诊断严重依赖于血清肌酐测量，因此通常在原始损伤后48-72小时进行。有一个明确和迫切的需要，以确定与阿基患者早期，最好的方法被认为是涉及识别生物标志物和他们的验证在人体临床试验。

DESCRIPTION (provided by applicant): The challenge area (03-DK-102) is the development and validation of novel, noninvasive methods to detect and monitor disorders of relevance to NIDDK at early stages of disease before major organ damage and dysfunction has occurred. Novel diagnostic methodologies relevant to disorders that are currently difficult to detect early in the course of disease and/or that require invasive procedures (such as tissue or organ biopsies) are of highest priority. The specific challenge topic is the development of early, sensitive, non-invasive methods to diagnose acute kidney injury. We propose to examine utility of renalase, a novel molecule discovered in our laboratory, as an early and sensitive biomarker for acute kidney injury. Acute kidney injury (AKI) is a clinical condition commonly associated with sepsis, surgery, and certain drugs, and which affects up to 20% of hospitalized patients. Epidemiologic data indicate those who develop AKI are more likely to die than those who don't, and the risk is proportional to the severity of the renal injury and of the concomitant reduction in renal function. The development of effective treatment protocols for AKI has been hampered by the fact the diagnosis relies heavily of serum creatinine measurements, and is, therefore, often made 48-72 hours following the original insult. There is a clear and pressing need to identify patients with AKI early, and the best approach is believed to involve the identification biomarkers and their validation in human clinical trials. Renalase is an amine oxidase that metabolizes catecholamines such as dopamine, epinephrine and norepinephrine. It is synthesized by the renal proximal tubule, secreted in blood and continuously excreted in urine in the basal state. Renalase levels can be measured either by Western blot or ELISA. Preliminary data suggest that renalase is a novel biomarker for AKI. Moderately severe ischemic insults (global ischemia for 45 min), caused a dramatic and long-lasting decrease in urinary renalase excretion. These data are very exciting and suggest that urinary renalase may be an early biomarker for ischemic AKI. The main goal of this proposal is test the hypothesis that urinary renalase can serve as an early and sensitive biomarker for AKI in rodents, and that renalase administration is a useful therapeutic option to treat AKI in rodents. If the proposed studies are successful, future studies (not part of this proposal) will aim to validate renalase as a biomarker of AKI in humans using the TRIBE-AKI database and or similar available databases, and to test the therapeutic utility of recombinant renalase in AKI in humans. PUBLIC HEALTH RELEVANCE: Acute kidney injury (AKI), a clinical condition commonly associated with sepsis, surgery, and certain drugs, affects up to 20% of hospitalized patients and is associated with increased mortality. The development of effective treatment protocols for AKI has been hampered by the fact the diagnosis relies heavily of serum creatinine measurements, and is, therefore, often made 48-72 hours following the original insult. There is a clear and pressing need to identify patients with AKI early, and the best approach is believed to involve the identification biomarkers and their validation in human clinical trials.