Biomarker Profiles for Prediction and Diagnosis of Post-Transplant Renal Injury

用于预测和诊断移植后肾损伤的生物标志物谱

• 批准号: 7804107
• 负责人: Michael M Abecassis
• 金额: $ 10万
• 依托单位: RULES-BASED MEDICINE, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7804107
• 关键词: Abdomen; Acute; Address; Age; Atrophic; Benchmarking; Biological Markers; Biopsy; Blood; Blood Proteins; Calcineurin inhibitor; Cells; Chest; Chronic; Chronic Kidney Failure; Chronic Kidney Insufficiency; Chronic rejection of renal transplant; Clinical; Collaborations; Complex; Complication; Creatinine; Data; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Drug toxicity; Early Diagnosis; Ensure; Enzyme-Linked Immunosorbent Assay; Etiology; Event; Evolution; Face; Fibrosis; Functional disorder; Gender; Goals; Heart Transplantation; Hypertension; Immune; Immune Targeting; Immunity; Immunoassay; Immunosuppression; Immunosuppressive Agents; Individual; Inflammation; Inflammatory; Injury; Ischemia; Kidney; Kidney Failure; Kidney Transplantation; Laboratories; Literature; Liver; Measures; Mediating; Medical; Medicine; Metabolic syndrome; Methods; Metric; Modeling; Monitor; Nephrotoxic; Organ Transplantation; Outcome; Pain; Patients; Pattern; Pharmaceutical Preparations; Phase; Plasma; Plasma Proteins; Population Study; Prediabetes syndrome; Predictive Value; Process; Proteins; Proteomics; Protocols documentation; Quantitative Evaluations; Renal function; Reperfusion Therapy; Research; Research Infrastructure; Research Institute; Risk; Risk Factors; Running; Safety; Sampling; Screening procedure; Sensitivity and Specificity; Serum; Signal Transduction; Small Business Innovation Research Grant; Staging; Technology; Testing; Therapeutic; Therapeutic Intervention; Therapeutic immunosuppression; Time; Tissues; Toxic effect; Transplant Recipients; Transplantation; Tubular formation; Universities; Validation; Variant; Work; base; chemokine; cost; cytokine; design; high risk; improved; injury prevention; interstitial; liver transplantation; minimally invasive; molecular marker; nephrogenesis; nephrotoxicity; novel; prevent; programs; prospective; protein expression; protein profiling; public health relevance; response; risk sharing; success; time use; tool; validation studies

DESCRIPTION (provided by applicant): Post-transplant renal injury is a mechanistically complex process that leads to progressive, chronic renal insufficiency and constitutes a major clinical barrier to the short- and long-term success of all organ transplants. There is a strong need for non-invasive, predictive and diagnostic biomarkers that can inform therapeutic decisions for Chronic Allograft Nephropathy/Interstitial Fibrosis with Tubular Atrophy (CAN/IFTA) in kidney recipients, Acute Rejection (AR) in both kidney and non-renal recipients and Chronic Kidney Disease (CKD) in non-renal recipients. In collaboration with Northwestern University (NW), and The Scripps Research Institute (TSRI), Rules-Based Medicine (RBM) proposes a quantitative proteomics approach, using comprehensive Multi-Analyte Profiles (MAPs), to compare the protein profiles in plasma samples obtained from kidney, liver and heart transplant patients and identify both common and unique biomarker signatures and mechanisms of immunity, drug toxicity and the concomitant medical risk factors that drive renal injury. A number of research groups are performing detailed studies to evaluate the expression of individual biomarkers associated with renal injury for use as an objective clinical tool. However, the standard method for measuring plasma or serum levels of cytokines, chemokines or other biomarkers is to measure them one at a time using Enzyme-Linked Immunosorbent Assay. One-at-a-time assessment of each putative biomarker incurs considerable time, cost and sample volume. Clearly, no single molecular marker, or small group of markers, will be able to accurately classify individuals at highest risk. The ability to systematically identify protein profiles, predict risk of clinical events, evaluate therapeutic response, and define underlying mechanisms is thereby limited severely. RBM has developed MAPs to screen large numbers of biomarkers in parallel, using bead-based multiplex immunoassays. This technology provides a quantitative evaluation of protein expression patterns using very small sample volumes (10-20 5L) with a dynamic range of fg/mL to mg/mL. This technology is well suited for screening large numbers of markers in parallel to identify protein profiles associated with renal injury. Using this approach in a recent preliminary study, RBM, NW and TSRI have discovered a protein profile for AR with a 79% Predictive Accuracy, and a profile for CAN/IFTA (Banff 1,2,3) with a 91% Predictive Accuracy. We have also discovered a kidney injury panel that has a 94% Predictive Accuracy for kidney patients with transplant dysfunction due to CAN/IFTA, 82% with biopsy-proven AR and 82% for liver transplant recipients with renal insufficiency due to CNI toxicity, hypertension and metabolic syndromes. In this Fast-Track program, we propose to test, refine and validate these profiles. The goal will be to improve the long-term outcome of recipients of thoracic and abdominal organ transplants by developing novel biomarker patterns that clinicians can use to predict, diagnose and monitor transplant outcomes. PUBLIC HEALTH RELEVANCE: Post-transplant renal injury is a mechanistically complex process that leads to progressive, chronic renal insufficiency and constitutes a major clinical barrier to the short- and long-term success of all organ transplants. This program is designed to investigate what is common and what is unique in the biomarker signatures and mechanisms of immunity, drug toxicity and the concomitant medical risk factors that drive renal injury in kidney, liver and heart transplant patients. The goal will be to improve the long-term outcome of recipients of thoracic and abdominal organ transplants by developing novel biomarker patterns that clinicians can use to predict, diagnose and monitor transplant outcomes.

描述（由申请人提供）：移植后肾脏损伤是一个机械复杂的过程，可导致渐进性，慢性肾功能不全，构成了所有器官移植的短期和长期成功的主要临床障碍。强烈需要非侵入性，预测性和诊断性生物标志物，可以为肾脏受体中的慢性同种异体移植肾病/间质性纤维化提供治疗决定，并在肾脏受体中伴有肾脏抑制作用（AR）接受肾脏和非肾脏和非慢性小子病（CKD）（CKD）（ckd）的急性抑制（AR）。与西北大学（NW）和Scripps研究所（TSRI）合作，基于规则的医学（RBM）使用全面的多分析物概况（MAP）提出了一种定量蛋白质组学方法（MAPS），以比较来自肾脏和心脏病患者的蛋白质样品中的蛋白质概况，并确定了肾脏和心脏移植的生物符号，并鉴定出了独特的生物迹象，并鉴定出了独特的生物迹象，并与之相比以及驱动肾脏伤害的伴随医疗危险因素。许多研究小组正在进行详细的研究，以评估与肾脏损伤相关的单个生物标志物的表达，以用作客观的临床工具。但是，测量细胞因子，趋化因子或其他生物标志物血浆或血清水平的标准方法是使用酶联免疫吸附测定法一次测量它们。对每个推定的生物标志物的一次时间评估会产生相当大的时间，成本和样本量。显然，没有单个分子标记或一小部分标记将能够准确地对处于最高风险的个人进行分类。因此，系统地识别蛋白质谱，预测临床事件的风险，评估治疗反应并定义潜在机制的能力受到严重限制。 RBM使用基于珠的多重免疫测定法开发了地图以并联筛选大量生物标志物。该技术使用非常小的样品体积（10-20 5L）对蛋白质表达模式进行定量评估，该样品量（10-20 5L）具有动态范围为FG/mL至mg/ml。该技术非常适合筛选大量标记，以识别与肾脏损伤相关的蛋白质曲线。在最近的一项初步研究中，使用这种方法，RBM，NW和TSRI发现了具有79％预测精度的AR的蛋白质谱，并且具有91％的预测精度的CAN/IFTA（Banff 1,2,3）的概况。我们还发现了一个肾脏损伤面板，该肾脏损伤面板具有94％的预测准确性，可为CAN/IFTA引起的移植功能障碍的肾脏患者，活检表现为82％，肝移植受者为82％的肾脏毒性毒性，高血压，高血压和代谢综合症引起的肾脏不足。在这个快速轨道程序中，我们建议测试，完善和验证这些配置文件。目的是通过开发临床医生可以用来预测，诊断和监测移植结果的新型生物标志物模式来改善胸腔和腹部器官移植的长期结局。 公共卫生相关性：移植后肾脏损伤是一个机械上复杂的过程，可导致渐进式，慢性肾功能不全，构成了所有器官移植的短期和长期成功的主要临床障碍。该计划旨在研究什么是常见和什么是在生物标志物特征和免疫力，药物毒性和伴随医疗危险因素中造成肾脏，肝脏和心脏移植患者肾脏损伤的伴随医疗危险因素的独特性。目的是通过开发临床医生可以用来预测，诊断和监测移植结果的新型生物标志物模式来改善胸腔和腹部器官移植的长期结局。