Proteomic Predictors of Chronic Kidney Disease in Liver Transplant Recipients

描述(由申请人提供)：在所有非肾脏实体器官移植患者中，接受肝移植(LT)的患者慢性肾脏疾病(CKD)的发病率最高。慢性肾脏病在这一人群中的影响是巨大的，导致早期和晚期的发病率和死亡率以及肾脏器官资源的利用。肝移植提供者目前采用的策略是等到临床上肾功能障碍明显时再制定治疗策略，S往往为时已晚且无效--这是慢性肾脏病在这些患者中发生和进展的主要原因。如果更好地阐明肾损伤的机制，如果更成功地在临床建立之前发现肾损伤，这些方法可能很快就会得到改进。这项建议旨在确定是否可以借助检测亚临床肾损伤的预测性生物标记物来实现这一点，以便设计新的生物标记物引导的介入研究，以最大限度地减少这一人群中的慢性肾脏病。因此，我们的长期目标是利用预测性蛋白质组生物标记物来识别有CKD风险的LT受体 以及旨在降低这一风险的干预措施的合适人选。作为朝着这个方向迈出的一步， 这项R21应用的目的是确定肾功能保留的移植受者是否存在早期蛋白质组特征，这些受者最终在移植后1-5年内发展为慢性肾脏病。我们假设，这样一组血清蛋白可以预测CKD的未来发展，并识别需要早期干预策略的患者(例如，下一项建议)。这项研究有以下两个具体目标：目的1.确定肝移植术后早期是否存在亚临床肾损伤的蛋白质组学特征，以预测慢性肾脏疾病的发展。目的2.分析肝移植受者慢性肾脏疾病进展过程中蛋白质组特征的系列变化的意义。我们处于进行这项研究的独特位置是因为：1)从肾功能早期保留、随后发生或未发展为CKD的LT受者身上收集的生物样本[贝勒；NIAID CTOT14试验(U01 AI084146)]将随时可用于分析预测性签名；2)西北大学、贝勒、斯克里普斯和拥有获得许可的多分析蛋白质组图谱的蛋白质组公司Rules Based Medicine(RBM)之间已经建立了合作关系，所有这些都具有实现我们的目标的不同角色。该方法将在独立的队列(贝勒和CTOT14生物信息库)中初步测试和验证LT后早期蛋白质组发现小组作为即将到来的CKD的预测。然后，我们将测试系列CTOT14样本，以评估GFR测量的蛋白质特征的演变，提供对肾脏损伤的洞察和完善预测。这一R21将专门为CKD LT提供资金 CTOT14中的蛋白质组学研究不再可用，因为RBM失去了SBIR，这是最初的资助机制。完成后，我们将验证预测性签名，通过促进在这一人群中保护肾功能的方法的前瞻性、生物标记物驱动的研究来改变这一领域。1

DESCRIPTION (provided by applicant): Liver transplant (LT) recipients have amongst the highest rates of chronic kidney disease (CKD) of all non- renal solid organ transplant recipients. The impact of CKD in this population is substantial, leading to early and late morbidity and mortality and kidney organ resource utilization. The strategy that LT providers currently employ, which is to wait until renal dysfunction is clinically apparent to institute a treatment strategy, s often too late and ineffective - a major reason why CKD develops and progresses in these patients. These approaches might be imminently improved if mechanisms of renal injury were better clarified and if more successful, proactive strategies to detect renal injury before it is clinically established were available. This proposal aims to determine whether this can be done with the aid of predictive biomarkers detecting subclinical renal injury so as to design novel biomarker-guided interventional studies to minimize CKD in this population. Our long-term goal is thus to utilize predictive proteomic biomarkers that will identify LT recipients at risk for CKD and suitable candidates for interventions aimed at reducing this risk. As a step in that direction, the objective of this R21 application is to determine if early proteomic signatures are present in LT recipients with preserved renal function who eventually develop CKD within 1-5 years of LT. We hypothesize that such an array of serum proteins can predict the future development of CKD and identify patients in need of early interventional strategies (e.g. the next proposal). The study is planned with the following two specific aims: Aim 1. To determine if a proteomic signature of subclinical renal injury is present early after LT that predicts the development of chronic kidney disease. Aim 2. To analyze the significance of serial changes in proteomic signatures during the course of chronic kidney disease progression in liver transplant recipients. We are uniquely positioned to conduct this research because: 1) biosamples [Baylor; NIAID CTOT14 trial (U01 AI084146)] collected from LT recipients with early preserved renal function who subsequently did or did not develop CKD will be readily available to analyze for predictive signatures; 2) an established collaboration exists between the Northwestern, Baylor, Scripps and a proteomics company Rules Based Medicine (RBM) who have the licensed multi-analyte proteomic panels - all with distinct roles to accomplish our goals. The approach will be to initialy test and validate early post-LT proteomic discovery panels as predictive of impending CKD in independent cohorts (Baylor & CTOT14 biorepositories). We will then test serial CTOT14 samples to evaluate the evolution of protein signatures with GFR measures, providing insights into renal injury and refining prediction.This R21 will specifically provide funding for the CKD LT proteomics research in CTOT14 that is no longer available, as RBM lost the SBIR that was the original funding mechanism. Upon completion, we will have validated predictive signatures that could transform the field by promoting proactive, biomarker-driven investigations of approaches to preserve renal function in this population. 1