Endothelial microparticles in patients with kidney transplants

肾移植患者的内皮微粒

• 批准号: 8188907
• 负责人: SERGEY BRODSKY
• 金额: $ 19.06万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-23 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8188907
• 关键词: Acute; Allografting; Animals; Antibodies; Antigens; Apoptotic; Biological Markers; Biopsy; Blood Vessels; Blood capillaries; Cell Surface Proteins; Cell physiology; Cells; Cirrhosis; Creatinine; Data; Diagnosis; End stage renal failure; Endothelial Cells; Endothelium; Failure; Functional disorder; Goals; Gold; Graft Survival; Hepatitis C; Histologic; Immunosuppression; In Vitro; Kidney; Kidney Transplantation; Major Histocompatibility Complex; Measures; Mediating; Membrane; Operative Surgical Procedures; Organ Transplantation; Pathogenesis; Pathology; Patients; Pattern; Pilot Projects; Play; Procedures; Production; Proteins; Quality of life; Role; Serum; Solid; Staining method; Stains; Stress; Surrogate Markers; Techniques; Testing; Transplant Recipients; Vesicle; allograft rejection; base; capillary; cell type; clinically significant; complement C4d; improved; kidney allograft; liver transplantation; novel; novel marker; research clinical testing

DESCRIPTION (provided by applicant): This proposal seeks to establish levels of circulating endothelial microparticles (EMP) as a novel biomarker of allograft rejection in the setting of kidney transplantation. Endothelial cells (EC) play an important role in the pathogenesis of allograft dysfunction and rejection. With improved immunosuppression and surgical technique, graft survival has significantly increased. Nevertheless, allograft rejection remains one of the main causes for allograft failure. The endothelium is one of the main targets in allograft rejection, especially antibody-mediated rejection (AMR). Typically, renal allograft function is evaluated by serum creatinine (SC) levels. Unfortunately, SC level elevation is a non-specific marker of renal allograft dysfunction, and it may occur in many different conditions. The "gold standard" test for the assessment of allograft rejection is renal allograft biopsy, which is an invasive, expensive and relatively risky procedure. The patterns of acute cellular rejection (ACR) are well-documented and broadly recognized. However, diagnosis of AMR is one of the most challenging in renal pathology. Peritubular capillary (PTC) C4d staining is one of the markers of AMR. Still, some kidney biopsies show C4d staining without histologic findings of AMR or ACR. Recently, evidence that some forms of AMR may be negative for PTC C4d staining has been described. Based on these data, the need for a reliable and clinically significant marker of allograft rejection is emerging. Microparticles are small membrane vesicles shed by different cell types, which contain cell surface proteins and cytoplasmic components of the original cell. The microparticle production is a part of normal cell function, but it increases by apoptotic cells and cells under stress. Others and we had previously demonstrated that levels of circulating EMP may be used as a surrogate marker of EC dysfunction. Recent studies have indicated changes in circulating EMP levels in patients with solid organ transplants, including kidneys. We demonstrated that circulating EMP levels, initially elevated in patients with Hepatitis C cirrhosis, were decreased to the levels seen in healthy people two weeks after liver transplantation. This data suggests that the levels of circulating EMP may be useful as a biomarker of EC function in patients with solid organ transplants. Based on these findings, we hypothesize that 1) an elevation in circulating EMP levels may be a novel marker of renal allograft rejection; 2) EMP produced by the renal allograft endothelium are different by their protein composition from EMP produced by the recipient endothelium; therefore, the former may be used as the biomarker of EC function of the renal allograft. Our hypotheses will be tested under two specific aims: 1) evaluate if the levels of circulating endothelial microparticles can be used as a marker of allograft rejection in patients with kidney transplants; 2) undertake a pilot study to investigate if the pool of circulating EMP may be further separated in order to distinguish between the microparticles produced by the recipient and allograft endothelium. Conclusions: This R21 is the essential step to advance the study of EMP as the novel marker of rejection in renal transplant patients. PUBLIC HEALTH RELEVANCE: Renal transplantation saves thousands of lives and improves quality of life in patients with end stage renal disease. The main cause of renal allograft failure is rejection. The endothelium is the internal layer in blood vessels and it is one of the main targets during allograft rejection. Microparticles are small vesicles shed by many cells when they are functioning abnormally, including the endothelium. We described earlier that the number of endothelial microparticles reflects endothelial cell function in experimental settings in vitro and in animals. We propose that number of microparticles shed by the endothelium in the renal allograft increases during rejection and this may be used as a novel marker for rejection. Our long term goal is to develop a novel, reliable and useful clinical test to recognize rejection in patients with renal transplants.

描述（由申请人提供）：该提案旨在在肾脏移植的情况下建立循环内皮微粒（EMP）作为同种异体移植排斥的新生物标志物。内皮细胞（EC）在同种异体功能障碍和排斥反应的发病机理中起重要作用。随着免疫抑制和手术技术的改善，移植物存活率显着增加。然而，同种异体移植排斥仍然是同种异体移植失败的主要原因之一。内皮是同种异体移植排斥反应的主要靶标之一，尤其是抗体介导的排斥反应（AMR）。通常，通过血清肌酐（SC）水平评估肾脏同种异体移植功能。不幸的是，SC水平升高是肾脏同种异体功能障碍的非特异性标记，并且可能在许多不同的条件下发生。评估同种异体移植排斥的“金标准”测试是肾脏同种异体移植活检，这是一种侵入性，昂贵且相对危险的手术。急性细胞排斥（ACR）的模式有充分的文献记录和广泛认可。但是，AMR的诊断是肾脏病理中最具挑战性的诊断之一。周围毛细管（PTC）C4D染色是AMR的标记之一。尽管如此，一些肾脏活检仍显示C4D染色，没有AMR或ACR的组织学发现。最近，已经描述了某些形式的AMR对PTC C4D染色可能为阴性的证据。基于这些数据，出现了对同种异体移植排斥的可靠且具有临床意义的标志物的需求。 微粒是由不同细胞类型的小膜囊泡，其中包含原始细胞的细胞表面蛋白和细胞质成分。微粒产生是正常细胞功能的一部分，但在压力下凋亡细胞和细胞增加。其他人，我们以前曾证明，循环EMP水平可以用作EC功能障碍的替代标记。最近的研究表明，包括肾脏在内的固体器官移植患者的循环EMP水平发生变化。我们证明，肝炎肝硬化患者最初升高的循环EMP水平降低到肝移植后两周健康人中看到的水平。该数据表明，循环EMP的水平在具有固体器官移植的患者中可以作为EC功能的生物标志物有用。基于这些发现，我们假设1）循环EMP水平的升高可能是同种异体移植排斥的新颖标志； 2）同种异体移植内皮产生的EMP与受体内皮产生的EMP不同。因此，前者可以用作同种异体移植的EC功能的生物标志物。我们的假设将在两个具体目的下进行检验：1）评估是否可以将循环内皮微粒的水平用作肾脏移植患者的同种异体移植排斥的标志； 2）进行一项试点研究，以研究是否可以进一步分离循环EMP的池，以区分受体和同种异体内皮产生的微粒。 结论：该R21是推进EMP研究为肾移植患者排斥的新标志的重要步骤。 公共卫生相关性：肾脏移植可挽救数千种生命，并改善终阶段肾脏疾病患者的生活质量。肾脏同种异体失败的主要原因是排斥。内皮是血管中的内层，它是同种异体移植排斥期间的主要靶标之一。微粒是许多细胞异常发挥作用（包括内皮）时的小囊泡。我们前面描述的是，内皮微粒的数量反映了体外和动物实验环境中的内皮细胞功能。我们提出，在排斥反应过程中，肾脏同种异体移植物中由内皮脱落的微粒数量可以用作排斥的新标记。我们的长期目标是开发一种新颖，可靠和有用的临床测试，以识别肾移植患者的排斥。