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

描述（由申请人提供）：移植后肾损伤是一个机制复杂的过程，可导致进行性慢性肾功能不全，是所有器官移植短期和长期成功的主要临床障碍。对于肾脏受体慢性同种异体肾病/间质纤维化伴小管萎缩（can /IFTA）、肾脏和非肾脏受体急性排斥反应（AR）以及非肾脏受体慢性肾脏疾病（CKD）的治疗决策，迫切需要无创、预测性和诊断性的生物标志物。基于规则的医学（RBM）与西北大学（NW）和斯克里普斯研究所（TSRI）合作，提出了一种定量蛋白质组学方法，使用全面的多分析物图谱（MAPs）来比较肾脏、肝脏和心脏移植患者血浆样本中的蛋白质图谱，并确定常见和独特的生物标志物特征以及驱动肾损伤的免疫、药物毒性和伴随医疗风险因素的机制。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，并将其作为客观的临床工具。然而，测量血浆或血清中细胞因子、趋化因子或其他生物标志物水平的标准方法是使用酶联免疫吸附测定法一次测量一个。对每一种假定的生物标志物进行一次评估需要花费大量的时间、成本和样本量。显然，没有单一的分子标记，或一小群标记，能够准确地对高危人群进行分类。因此，系统地识别蛋白质谱、预测临床事件风险、评估治疗反应和确定潜在机制的能力受到严重限制。RBM已经开发出MAPs，使用基于脑珠的多重免疫测定法并行筛选大量生物标志物。该技术使用非常小的样品体积（10- 205l），动态范围为fg/mL至mg/mL，提供蛋白质表达模式的定量评估。该技术非常适合于平行筛选大量标记物，以识别与肾损伤相关的蛋白质谱。在最近的一项初步研究中，RBM、NW和TSRI使用这种方法发现了AR的蛋白质谱，预测准确率为79%，CAN/IFTA （Banff 1,2,3）的蛋白质谱预测准确率为91%。我们还发现了一个肾损伤小组，对因CAN/IFTA导致的肾移植功能障碍患者的预测准确率为94%，对活检证实的AR患者的预测准确率为82%，对因CNI毒性、高血压和代谢综合征导致肾功能不全的肝移植患者的预测准确率为82%。在这个快速通道程序中，我们建议测试、改进和验证这些配置文件。目标是通过开发新的生物标志物模式来改善胸腔和腹腔器官移植接受者的长期预后，临床医生可以使用这些生物标志物模式来预测、诊断和监测移植结果。

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.