Urine biomarkers of lupus nephritis pathology and response to therapy

狼疮性肾炎病理学的尿液生物标志物和治疗反应

• 批准号: 7932421
• 负责人: JAMES C OATES
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932421
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Adrenal Cortex Hormones; Affect; African American; American; Antigen-Antibody Complex; Automobile Driving; Baltimore; Biological Assay; Biological Markers; Biological Neural Networks; Biopsy; Blood Pressure; Caucasians; Caucasoid Race; Characteristics; Classification; Clinic; Clinical; Clinical Trials; Color; Complement; Complex; Consensus; Coupled; Cyclophosphamide; Data; Decision Making; Detection; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Disease Marker; Drug toxicity; Electron Microscopy; Elements; Enzyme-Linked Immunosorbent Assay; Excretory function; Exposure to; Female; Fibrosis; Funding; Future; Glomerulonephritis; Goals; Gold; Growth Factor; Health; Heterogeneity; High Pressure Liquid Chromatography; Histopathology; Hypertension; Immune response; Immunoassay; Individual; International; Intravenous; Kidney; Kidney Diseases; Kidney Failure; Lesion; Link; Literature; Logistic Regressions; Lupus Nephritis; Machine Learning; Measures; Mediating; Methods; Minority; Modeling; Monitor; Nature; Neoadjuvant Therapy; Nephritis; Nephrology; Online Systems; Oral; Outcome; Outcome Measure; Oxidative Stress; Pathogenesis; Pathology; Pathway Analysis; Pathway interactions; Patient Care; Patients; Performance; Phase; Physiologic pulse; Population; Population Study; Post-Translational Protein Processing; Preparation; Principal Investigator; Process; Production; Proliferative Glomerulonephritis; Proteins; Qualifying; Regression Analysis; Renal function; Research; Research Personnel; Rheumatology; Severity of illness; Societies; Staging; Study models; System; Systemic Lupus Erythematosus; Techniques; Technology; Testing; Therapeutic; Time; Training; Treatment Failure; Treatment Protocols; Tyrosine; Urine; Validation; Veterans; Woman; Work; base; candidate marker; chemokine; clinical decision-making; cohort; college; cytokine; design; drug development; health disparity; mathematical model; meetings; novel; novel strategies; patient population; population health; predictive modeling; prevent; programs; prospective; response; rheumatologist; standard care; therapeutic target; tool; treatment response; urinary

DESCRIPTION (provided by applicant): Lupus nephritis (LN) results in renal failure in up to 42% of patients after five years. However, traditional biomarkers and clinical indicators of treatment response often cannot detect treatment failure until irreversible damage to the kidneys has occurred. Therefore, a more reliable means of determining diagnosis and response to induction therapy in LN is needed. The goals of this project are to provide clinicians and investigators with 1) a non-invasive, reliable tool for diagnosis of International Society of Nephrology/Renal Pathology Society (ISN/RPS) class (Class) in LN, 2) a short-term marker of long-term response to therapy, 3) validated assays of biomarkers for clinical use, and 4) hypotheses about mechanisms of response to therapy that can be used as future therapeutic targets. During the first three years of funding, biomarker discovery efforts provided preliminary data that has focused efforts on a limited number of candidate markers. Markers of reactive intermediate production also showed promise as biomarkers. Links between candidate biomarkers and oxidative stress in LN were suggested by our preliminary data and pathways analysis. In preliminary studies, models using this narrowed set of markers had increased predictive power in diagnosing Class and predicting response to therapy over traditional biomarker or single biomarkers models. We hypothesize that changes in expression of and reactive intermediate-induced post-translational modifications of urinary proteins will serve as biomarkers of Class and response to therapy in LN. To address these hypotheses, the following Specific Aims are proposed: 1) Create and validate models of urine biomarkers diagnostic of International Society of Nephrology/Renal Pathology Society (ISN/RPS) biopsy class (Class) in lupus nephritis (LN), 2) Create and validate models of urine biomarkers predictive of renal response to induction therapy in LN, and 3) Develop and validate biomarker assays for clinical use. Subjects will derive from the Charleston and Baltimore inception cohorts and the Genentech LUNAR study population. ISN/RPS class of nephritis will be determined at entry, and outcomes at one year after start of induction therapy will be characterized by the American College of Rheumatology and Systemic Lupus Erythematosus International Cooperating Clinics renal response criteria. Urine will be collected at zero and three months after entry. Candidate low abundance proteins (chemokines, growth factors, cytokines, and renal damage markers selected from discovery analysis in the first funding period) will be quantitated by the Luminex bead assay and ELISA. Post-translational modifications of urine protein tyrosines (Tyr) indicative of exposure to reactive intermediates will be detected by high performance liquid chromatography-electrochemical detection (HPLC-EC). Levels of individual markers at baseline (for Aim 1) and baseline and three months (for Aim 2) will be used to create a mathematical models (by artificial neural network (ANN) that use the levels of surrogate urine protein markers to: 1) diagnose Class of LN at baseline and 2) predict response therapy at one year. Due to the technical nature of machine learning, a reviewer familiar with ANN analysis is requested. In the third Aim, an immunoassay for reactive-intermediate-modified Tyr will be developed, and all biomarker immunoassays will undergo method validation suitable for formal biomarker qualification. This latter step is essential to rapid acceptance and application of the findings of this study to the clinic. Pathways analysis will be used to explore mechanistic interactions between biomarkers deemed predictive in the first two aims. Hypotheses regarding mechanisms of disease activity, damage, and response to therapy will be identified that could be exploited with targeted therapies. This study is unique in 1) the size, diversity, and rigorous characterization of the population used to train and validate the predictive models and 2) its use of novel and well described biomarkers representing diverse pathogenic mechanisms to be tested in a single model. The long-term goal is to provide clinicians with a qualified biomarker panel coupled with a web-based predictive tool for more accurate diagnosis and therapeutic monitoring of LN. PUBLIC HEALTH RELEVANCE: Narrative-Relevance to Veterans Health. Lupus nephritis affects a growing population of women and women of color in the veteran population, and health disparities among minorities and women are a priority for Veterans Health research initiatives. The markers identified for poor outcomes in women with lupus nephritis will give clinicians and researchers enhanced and necessary tools for drug development and patient care by providing noninvasive markers of disease and short term therapeutic response indicators. The biomarker qualification techniques used in this study are broadly applicable to other renal diseases such as diabetes and hypertension, both of which are prevalent in the veteran population and are associated with poor outcomes. Thus, the results of this study could advance the progress of non-invasive renal monitoring for advancing glomerulonephritis in a number of diseases.

描述（由申请人提供）： 狼疮性肾炎 (LN) 会导致高达 42% 的患者在 5 年后出现肾功能衰竭。然而，传统的生物标志物和治疗反应的临床指标通常无法检测治疗失败，直到肾脏发生不可逆转的损伤。因此，需要一种更可靠的方法来确定 LN 的诊断和诱导治疗的反应。该项目的目标是为临床医生和研究人员提供 1) 一种无创、可靠的工具，用于 LN 中国际肾脏病学会/肾脏病理学会 (ISN/RPS) 分级 (Class) 的诊断，2) 短期诊断长期治疗反应的标志物，3）临床使用的生物标志物的验证测定，以及4）关于可用作未来治疗靶点的治疗反应机制的假设。在资助的前三年中，生物标志物发现工作提供了初步数据，这些数据将工作重点集中在有限数量的候选标志物上。反应中间体产生的标记物也显示出作为生物标记物的前景。我们的初步数据和通路分析表明候选生物标志物与 LN 氧化应激之间的联系。在初步研究中，与传统生物标志物或单一生物标志物模型相比，使用这组缩小的标志物的模型在诊断类别和预测治疗反应方面具有更高的预测能力。我们假设尿蛋白表达的变化和反应性中间体诱导的翻译后修饰将作为 LN 类型和治疗反应的生物标志物。为了解决这些假设，提出以下具体目标：1) 创建并验证国际肾脏病学会/肾脏病理学会 (ISN/RPS) 狼疮性肾炎 (LN) 活检类别 (Class) 的尿液生物标志物诊断模型，2)创建和验证预测 LN 诱导治疗肾脏反应的尿液生物标志物模型，以及 3) 开发和验证临床使用的生物标志物测定。受试者将来自查尔斯顿和巴尔的摩初始队列以及基因泰克 LUNAR 研究人群。 ISN/RPS 肾炎类别将在入组时确定，诱导治疗开始一年后的结果将按照美国风湿病学会和系统性红斑狼疮国际合作诊所肾脏反应标准进行表征。尿液将在入境后零个月和三个月收集。候选低丰度蛋白质（从第一个资助期的发现分析中选择的趋化因子、生长因子、细胞因子和肾损伤标记物）将通过 Luminex 珠测定和 ELISA 进行定量。尿蛋白酪氨酸 (Tyr) 的翻译后修饰表明暴露于反应性中间体，将通过高效液相色谱-电化学检测 (HPLC-EC) 进行检测。基线（针对目标 1）以及基线和三个月（针对目标 2）的各个标记物水平将用于创建数学模型（通过人工神经网络 (ANN)，该模型使用替代尿蛋白标记物水平来：1）在基线时诊断 LN 类别，并 2) 预测一年后的缓解治疗。由于机器学习的技术性质，需要熟悉 ANN 分析的审稿人。在第三个目标中，将开发一种针对反应性中间体修饰的 Tyr 的免疫测定法，并且所有生物标志物免疫测定法将接受适合正式生物标志物鉴定的方法验证。后一步对于快速接受本研究结果并将其应用于临床至关重要。路径分析将用于探索被认为可预测前两个目标的生物标志物之间的机械相互作用。将确定有关疾病活动、损害和治疗反应机制的假设，这些假设可用于靶向治疗。这项研究的独特之处在于：1）用于训练和验证预测模型的人群的规模、多样性和严格特征；2）它使用了新颖且描述良好的生物标志物，代表了要在单一模型中测试的多种致病机制。长期目标是为临床医生提供合格的生物标志物组合以及基于网络的预测工具，以更准确地诊断和治疗监测 LN。 公共卫生相关性： 叙述与退伍军人健康的相关性。狼疮性肾炎影响退伍军人群体中越来越多的女性和有色人种女性，少数族裔和女性之间的健康差异是退伍军人健康研究计划的优先事项。通过提供非侵入性的疾病标记和短期治疗反应指标，确定的狼疮性肾炎女性预后不良的标记将为临床医生和研究人员提供增强和必要的药物开发和患者护理工具。本研究中使用的生物标志物鉴定技术广泛适用于其他肾脏疾病，例如糖尿病和高血压，这两种疾病在退伍军人群体中普遍存在，并且与不良预后相关。因此，这项研究的结果可以推动非侵入性肾脏监测的进展，以预防多种疾病中进展性肾小球肾炎。