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复杂的机械过程，会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。对非侵入性、预测性和诊断性生物标志物的需求非常迫切，这些生物标志物可以为肾移植受者的慢性移植肾病/间质纤维化伴肾小管萎缩(CAN/IFTA)、肾和非肾移植受者的急性排斥(AR)以及非肾移植受者的慢性肾脏疾病(CKD)的治疗决策提供信息。在西北大学(NW)和斯克里普斯研究所(TSRI)的合作下，基于规则的医学(RBM)提出了一种定量蛋白质组学方法，使用全面的多分析图谱(MAP)来比较肾、肝和心脏移植患者的血浆样本中的蛋白质图谱，并确定共同和独特的生物标志物特征和免疫、药物毒性以及导致肾损伤的伴随医疗风险因素的机制。一些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记物的表达，以用作客观的临床工具。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试验一次测量一个。对每个假定的生物标志物进行一次一次的评估需要大量的时间、成本和样本量。显然，没有任何单一的分子标记或一小群标记能够准确地对高危个体进行分类。因此，系统地识别蛋白质谱、预测临床事件的风险、评估治疗反应和确定潜在机制的能力受到严重限制。RBM已经开发了地图，使用基于珠子的多重免疫分析方法并行筛选大量生物标记物。这项技术使用非常小的样本体积(10-20 5L)，动态范围为fg/m L到mg/m L，提供了对蛋白质表达模式的定量评估。这项技术非常适合于并行筛选大量标记物，以识别与肾脏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的蛋白质图谱和CAN/IFTA(Banff 1，2，3)的蛋白质图谱，预测准确率分别为79%和91%。我们还发现了一个肾脏损伤专家小组，该小组对因CAN/IFTA导致移植功能障碍的肾脏患者具有94%的预测准确率，对经活检证实的AR具有82%的预测准确率，对于因CNI毒性、高血压和代谢综合征而导致肾功能不全的肝移植受者具有82%的预测准确率。在这个快速跟踪计划中，我们建议测试、改进和验证这些配置文件。目标将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的生物标记物模式来改善胸部和腹部器官移植受者的长期结果。 公共卫生相关性：移植后肾损伤是一个复杂的机械过程，会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。该计划旨在调查导致肾、肝和心脏移植患者肾损伤的生物标志物特征和免疫机制、药物毒性以及伴随的医疗风险因素中哪些是共同的，哪些是独特的。目标将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的生物标记物模式来改善胸部和腹部器官移植受者的长期结果。

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.