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

急性肾损伤中的肾酶：作为生物标志物和治疗剂的实用性

• 批准号: 7820609
• 负责人: Gary V. Desir
• 金额: $ 50万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7820609
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Affect; Area; Biological Markers; Biopsy; Blood; Cardiac; Cardiac Surgery procedures; Catecholamines; Clinical; Clinical Trials; Creatinine; Data; Databases; Development; Diagnosis; Disease; Dopamine; Enzyme-Linked Immunosorbent Assay; Epinephrine; Event; Excretory function; Functional disorder; Funding; Future; Gelatinase A; Goals; Hour; Human; Injury; Interleukin-18; Ischemia; Kidney; Laboratories; Measurement; Measures; Methodology; Methods; Monitor; Myocardial; Myocardial Ischemia; National Institute of Diabetes and Digestive and Kidney Diseases; Necrosis; Norepinephrine; Operative Surgical Procedures; Organ; Patients; Pharmaceutical Preparations; Procedures; Proximal Kidney Tubules; Rattus; Recombinants; Renal function; Reperfusion Therapy; Risk; Rodent; Rodent Model; Sensitivity and Specificity; Sepsis; Serum; Severities; Staging; Testing; Therapeutic; Therapeutic Agents; Tissues; Treatment Protocols; Tribes; United States National Institutes of Health; Urine; Validation; Western Blotting; amine oxidase; base; design; diagnostic accuracy; effective therapy; epidemiologic data; falls; high risk; improved; intravenous administration; mortality; mouse model; novel; novel diagnostics; public health relevance; renal ischemia; urinary

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.

描述（由申请人提供）：挑战领域（03-DK-102）是开发和验证新型非侵入性方法，以在主要器官损伤和功能障碍发生之前的疾病早期阶段检测和监测与 NIDDK 相关的疾病。与目前难以在病程早期检测和/或需要侵入性操作（例如组织或器官活检）的疾病相关的新型诊断方法是最优先考虑的。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（我们实验室发现的一种新分子）作为急性肾损伤的早期敏感生物标志物的效用。急性肾损伤 (AKI) 是一种通常与脓毒症、手术和某些药物相关的临床病症，影响高达 20% 的住院患者。流行病学数据表明，发生 AKI 的人比没有发生 AKI 的人更有可能死亡，而且风险与肾损伤和随之而来的肾功能下降的严重程度成正比。 AKI 有效治疗方案的制定因诊断严重依赖血清肌酐测量而受到阻碍，因此通常在最初损伤后 48-72 小时内进行诊断。早期识别 AKI 患者的需求是明确而紧迫的，据信最好的方法是识别生物标志物并在人体临床试验中对其进行验证。肾酶是一种胺氧化酶，可代谢儿茶酚胺，如多巴胺、肾上腺素和去甲肾上腺素。由肾近曲小管合成，分泌于血液中，并在基础状态下持续从尿中排出。肾酶水平可以通过蛋白质印迹或 ELISA 来测量。初步数据表明肾酶是 AKI 的一种新型生物标志物。中度严重的缺血性损伤（全身缺血 45 分钟）导致尿肾酶排泄急剧且持久的减少。这些数据非常令人兴奋，表明尿肾酶可能是缺血性 AKI 的早期生物标志物。该提案的主要目标是检验以下假设：尿肾酶可以作为啮齿类动物 AKI 的早期且敏感的生物标志物，并且肾酶给药是治疗啮齿类动物 AKI 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 AKI 的生物标志物，并测试重组肾酶在人类 AKI 中的治疗效用。 公共卫生相关性：急性肾损伤 (AKI) 是一种通常与脓毒症、手术和某些药物相关的临床病症，影响高达 20% 的住院患者，并与死亡率增加相关。 AKI 有效治疗方案的制定因诊断严重依赖血清肌酐测量而受到阻碍，因此通常在最初损伤后 48-72 小时内进行诊断。早期识别 AKI 患者的需求是明确而紧迫的，据信最好的方法是识别生物标志物并在人体临床试验中对其进行验证。