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

描述（由申请人提供）：移植后肾损伤是一种机制复杂的过程，可导致进行性慢性肾功能不全，并构成所有器官移植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，其可以为肾受体中的慢性移植物肾病/间质性纤维化伴肾小管萎缩（CAN/IFTA）、肾和非肾受体中的急性排斥（AR）以及非肾受体中的慢性肾病（CKD）的治疗决策提供信息。与西北大学（NW）和斯克里普斯研究所（TSRI）合作，基于规则的医学（RBM）提出了一种定量蛋白质组学方法，使用全面的多分析物谱（MAP），比较从肾脏，肝脏和心脏移植患者获得的血浆样本中的蛋白质谱，并识别常见和独特的生物标志物特征和免疫机制，药物毒性和导致肾损伤的伴随医学风险因素。许多研究小组正在进行详细的研究，以评估与肾损伤相关的个体生物标志物的表达，作为客观的临床工具。然而，用于测量细胞因子、趋化因子或其他生物标志物的血浆或血清水平的标准方法是使用酶联免疫吸附测定一次测量一种。对每种假定的生物标志物进行一次一次的评估会花费大量的时间、成本和样本量。显然，没有一个单一的分子标记，或一小群标记，将能够准确地分类个人在最高风险。因此，系统鉴定蛋白质谱、预测临床事件风险、评价治疗反应和确定潜在机制的能力受到严重限制。RBM已经开发了MAP，使用基于珠粒的多重免疫测定法平行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）提供蛋白质表达模式的定量评价，动态范围为fg/mL至mg/mL。该技术非常适合于平行筛选大量标记物以鉴定与肾损伤相关的蛋白质谱。在最近的一项初步研究中使用这种方法，RBM，NW和TSRI发现了AR的蛋白质谱，预测准确度为79%，CAN/IFTA（Banff 1，2，3）的谱预测准确度为91%。我们还发现了一种肾损伤面板，其对由于CAN/IFTA导致的移植功能障碍的肾脏患者具有94%的预测准确性，对活检证实的AR具有82%的预测准确性，对由于CNI毒性、高血压和代谢综合征导致的肾功能不全的肝移植受者具有82%的预测准确性。在这个快速通道计划中，我们建议测试，完善和验证这些配置文件。其目标是通过开发临床医生可用于预测、诊断和监测移植结果的新型生物标志物模式，改善胸部和腹部器官移植受者的长期结局。 公共卫生相关性：移植后肾损伤是一个机制复杂的过程，导致进行性慢性肾功能不全，并构成了所有器官移植短期和长期成功的主要临床障碍。该计划旨在研究生物标志物特征和免疫机制，药物毒性以及驱动肾脏，肝脏和心脏移植患者肾损伤的伴随医学风险因素中的常见和独特之处。其目标是通过开发临床医生可用于预测、诊断和监测移植结果的新型生物标志物模式，改善胸部和腹部器官移植受者的长期结局。

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.