SDF-1: A Diagnostic and Therapy-Specific Biomarker of AKI and CKD

SDF-1：AKI 和 CKD 的诊断和治疗特异性生物标志物

• 批准号: 7930478
• 负责人: Christof Westenfelder
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7930478
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Allogenic; Bilateral; Biological Markers; CXCL12 gene; CXCR4 gene; Cardiac Surgery procedures; Chronic; Chronic Kidney Failure; Clinical; Complex; Complication; Crush Injury; Development; Diagnosis; Diagnostic; Dialysis procedure; Disease; Disease model; Dose; Dyes; Early Diagnosis; Goals; Homing; Injury; Ischemia; Kidney; Laboratories; Mediating; Mesenchymal Stem Cells; Monitor; Morbidity - disease rate; Nephrectomy; Nephrotoxic; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Prevention; Public Health; Rattus; Recovery; Recovery of Function; Renal function; Reperfusion Therapy; Research; Resistance; Resources; Sepsis; Serum; Shock; Stem cells; Stromal Cell-Derived Factor 1; Stromal Cells; Study Section; Technology; Testing; Therapeutic; Time; Trauma; Treatment Cost; Up-Regulation; Urine; Veterans; Work; base; chemokine; combat; design; high risk; injured; mortality; noninvasive diagnosis; novel; novel diagnostics; paracrine; prevent; receptor; stem cell therapy; tool; urinary

DESCRIPTION (provided by applicant): SIGNIFICANCE and LONG-TERM OBJECTIVE: Acute kidney injury (AKI) is a largely treatment resistant complication encountered after major surgery, shock, sepsis, or administration of nephrotoxic drugs. The frequent progression of AKI to Chronic Kidney Disease (CKD), persistently high mortality rates (> 50 %) and treatment costs continue to make AKI a major public health problem, warranting the development of new therapies and diagnostic biomarkers, which is the goal of this proposal. HYPOTHESES: We have shown that mesenchymal stem cells (MSC) in AKI act renoprotectively through complex paracrine actions, and are currently testing this technology in a Phase I Clinical Trial. We showed 1st, that ischemic AKI results in prompt up regulation of the chemokine Stromal Derived Factor-1 (SDF-1 or CXCL12) in the kidney; 2nd, urinary SDF-1 levels rise dramatically at 2 hrs post AKI, and decline with recovery; and 3rd, because MSC express CXCR4, the SDF-1 receptor, high SDF-1 levels mediate their homing and thereby their renoprotective actions in AKI. We hypothesize, therefore, (1) that a rise in urinary levels of SDF-1 has utility as a new, early injury marker of AKI or potentially of "unresolved" AKI or progressive CKD; (2) that peak urine levels of SDF-1 after AKI identifies the time point at which MSC thereby is most effective; and (3) that elevated urinary SDF-1 levels, if indicative of persistent injury post AKI or in CKD, similarly signify that MSC therapy may be beneficial. SPECIFIC AIMS: The present work is designed to investigate whether monitoring of the urine for a rise of SDF-1 has utility (1) as a novel, diagnostic biomarker of AKI, and potentially progressive CKD; and (2) as a therapy-specific biomarker for AKI, i.e., for the identification of the time point when MSC therapy would be most effective, and potentially in progressive CKD. RESEARCH DESIGN and METHODS: Specific Aim 1: Utilizing bilateral I/R AKI and 5/6 nephrectomy CKD models in rats, temporal SDF-1 profiles in serum, kidney and urine are defined and correlated with function and NGAL levels. If urinary SDF-1 levels parallel renal SDF-1 levels and function, their monitoring will be sufficient for the early and noninvasive diagnosis of AKI. The influence of MSC therapy on renal SDF-1 and NGAL profiles is assessed. Similarly, in order to determine whether urinary SDF-1 levels can identify ongoing chronic renal injury, SDF-1 and NGAL profiles and renal function are monitored early and late after AKI and 5/6th nephrectomy. Specific Aim 2: Once SDF-1 profiles post AKI have been defined, it will be tested whether MSC therapy at peak urinary SDF-1 levels is most renoprotective, thereby potentially allowing a reduction in the dose of needed MSC. If it is demonstrated that persistently elevated urinary SDF-1 levels correlate with injury due to unresolved AKI or progressive CKD, the utility of MSC therapy in these conditions will be examined. PUBLIC HEALTH RELEVANCE: Project Narrative: Relevance to Veterans' Health A growing number of veterans require dialysis for the treatment of acute kidney injury (AKI) sustained during surgery, trauma, crush injuries, sepsis or from nephrotoxic dyes and drugs. The associated morbidity and mortality remains high and functional recovery, if it occurs, may take from days to weeks, thus consuming enormous resources. It is imperative that more effective therapeutic tools be developed to help prevent and combat this disease, which is the goal of this proposal.

描述（由申请人提供）： 意义和长期目标：急性肾损伤（AKI）是大手术、休克、脓毒症或服用肾毒性药物后遇到的一种很大程度上难以治疗的并发症。 AKI 频繁进展为慢性肾脏病 (CKD)、持续的高死亡率 (> 50%) 和治疗费用继续使 AKI 成为一个主要的公共卫生问题，需要开发新的疗法和诊断生物标志物，这也是本提案的目标。假设：我们已经证明，AKI 中的间充质干细胞 (MSC) 通过复杂的旁分泌作用发挥肾脏保护作用，目前正在 I 期临床试验中测试该技术。我们的第一点是，缺血性 AKI 会导致肾脏中趋化因子基质衍生因子 1（SDF-1 或 CXCL12）的迅速调节； 2、尿SDF-1水平在AKI后2小时急剧上升，并随着恢复而下降；第三，由于 MSC 表达 CXCR4（SDF-1 受体），高 SDF-1 水平介导它们的归巢，从而介导它们在 AKI 中的肾脏保护作用。因此，我们假设：(1) 尿液中 SDF-1 水平的升高可作为 AKI 或潜在的“未解决”AKI 或进行性 CKD 的新早期损伤标志物； (2) AKI后尿液中SDF-1的峰值水平确定了MSC最有效的时间点； (3) 尿液 SDF-1 水平升高，如果表明 AKI 后或 CKD 中存在持续性损伤，同样表明 MSC 治疗可能有益。具体目标：目前的工作旨在研究监测尿液中 SDF-1 的升高是否具有实用性 (1) 作为 AKI 和潜在进展性 CKD 的新型诊断生物标志物； (2) 作为 AKI 的治疗特异性生物标志物，即用于确定 MSC 治疗最有效的时间点，并且可能用于进展性 CKD。研究设计和方法： 具体目标 1：利用大鼠双侧 I/R AKI 和 5/6 肾切除 CKD 模型，定义血清、肾脏和尿液中的时间 SDF-1 谱，并将其与功能和 NGAL 水平相关联。如果尿液 SDF-1 水平与肾脏 SDF-1 水平和功能平行，则其监测将足以对 AKI 进行早期无创诊断。评估 MSC 治疗对肾 SDF-1 和 NGAL 谱的影响。同样，为了确定尿液 SDF-1 水平是否可以识别持续的慢性肾损伤，在 AKI 和 5/6 肾切除术后早期和晚期监测 SDF-1 和 NGAL 谱以及肾功能。具体目标 2：一旦确定 AKI 后的 SDF-1 概况，将测试尿 SDF-1 峰值水平下的 MSC 治疗是否最具肾脏保护作用，从而有可能减少所需 MSC 的剂量。如果证明尿 SDF-1 水平持续升高与未解决的 AKI 或进行性 CKD 造成的损伤相关，则将检查 MSC 治疗在这些情况下的效用。 公共卫生相关性： 项目叙述：与退伍军人健康的相关性 越来越多的退伍军人需要透析来治疗手术、创伤、挤压伤、败血症或肾毒性染料和药物造成的急性肾损伤 (AKI)。相关的发病率和死亡率仍然很高，如果发生功能恢复，可能需要几天到几周的时间，从而消耗大量资源。当务之急是开发更有效的治疗工具来帮助预防和对抗这种疾病，这也是该提案的目标。