Predictive Biomarkers for disease activity and organ damage in patients with lupus

狼疮患者疾病活动和器官损伤的预测生物标志物

基本信息

批准号：
9925731
负责人：
JAMES C OATES
金额：
$ 65.4万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-27 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9925731
关键词：
Address Age Aliquot Autoimmune Diseases Biological Assay Biological Markers Blood Categories Cell Compartmentation Cessation of life Chronic Chronic Kidney Failure Clinic Clinic Visits Clinical Clinical Management Clinical Services Clinical Trials Communities Complement Coupled Creatinine clearance measurement Custom DNA Development Diagnosis Disease Disease Outcome Disease susceptibility Elements End stage renal failure Failure Flare Future Genes Genetic Genetic Load Genetic Risk Genotype Goals Health Heterogeneity In complete remission Incidence Individual Inflammation Inherited Injury to Kidney Kidney Laboratories Laboratory Markers Lead Literature Longitudinal cohort Lupus Lupus Nephritis Maintenance Therapy Measurement Measures Medical Minority Modeling Monitor Morbidity - disease rate Neoadjuvant Therapy Nephrology Odds Ratio Ohio Organ Outcome Patient Care Patients Phenotype Plasma Probability Proteinuria Public Health Registries Research Resources Rheumatology Risk Sampling Sensitivity and Specificity Serum South Carolina Specificity Surrogate Markers Susceptibility Gene Systemic Lupus Erythematosus Testing Time Treatment Failure Universities Urine Vasculitis Woman base biomarker discovery biomarker panel cell injury clinical development clinically relevant cohort conventional therapy ds-DNA early detection biomarkers ethnic diversity experience improved indexing individual patient mortality mycophenolate mofetil novel novel marker predictive marker predictive modeling prospective random forest renal damage response risk prediction model risk variant screening sex therapy development treatment response validation studies

项目摘要

Abstract Lupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematosus (SLE) and is associated with significant morbidity and mortality. Current clinical laboratory markers lack sufficient sensitivity and specificity to optimize individual patient care creating a need to develop novel biomarkers for LN. To address this unmet need there has been a significant effort within the lupus research community to identify novel LN biomarkers, but to date none have been qualified for clinical use. We speculate that one of the important causes of these failures is that no single biomarker can account for the heterogeneity of SLE or LN. Under the hypothesis that multiple categories of biomarkers can represent different aspects of risk for LN, we propose to assess biomarkers that are classified into categories of disease susceptibility, systemic inflammation, and kidney compartment/cell injury to build models for risk prediction. Our objective is to develop composite biomarkers for early detection of renal flares, chronic renal damage, and treatment response of LN patients. To accomplish this goal we will use biospecimens from longitudinal observational cohorts and clinical trials that have well-annotated patient samples. The Medical University of South Carolina (MUSC) team therefore proposes to partner with the Ohio State University (OSU) team to combine each group's longitudinal SLE cohorts and create a well-phenotyped patient resource suited to biomarker discovery and large enough to adequately power validation studies. The combined OSU-MUSC cohort will have approximately 500 LN patients who have had rheumatology/nephrology clinic visits and biospecimens collected every two to six months for up to ten years. Using these samples, our collective team has already described several DNA, serum and urine biomarkers that are associated with disease activity, treatment response or organ damage in LN, and has considerable experience in developing biomarker panels for outcomes in LN. We have reviewed the last decade's literature, systematically ranked novel biomarkers, and propose to test the top performing LN biomarkers in this proposal to address whether: (i) Biomarkers associated with active LN can be used to predict impending renal flares in prospective longitudinal cohorts; (ii) Baseline measures of composite panels of urine or serum biomarkers can distinguish between who will and who will not achieve a renal response to one year of conventional therapy with mycophenolate mofetil; (iii) The development of genetic risk profiles of LN patients to identify those who are predisposed to develop chronic kidney damage. We will also compare biomarkers predictive of disease outcomes in LN to those in non-renal SLE, working towards developing LN specific vs general biomarker panels that are indicative of active inflammation and/or damage accrual. Our ultimate goal is to have validated LN predictors of sufficient sensitivity and specificity to be clinically relevant, and that can be easily assayed in most clinical service laboratories to improve patient care.

抽象的狼疮肾炎（LN）是全身性红斑狼疮（SLE）的最严重的表现之一，是与明显的发病率和死亡率相关。当前的临床实验室标记缺乏足够的敏感性和特异性以优化个体的患者护理，从而需要开发LN的新型生物标志物。到满足这种未满足的需求，狼疮研究界已经付出了巨大的努力来识别新型的LN生物标志物，但迄今为止，没有一个有资格用于临床使用。我们推测其中之一这些失败的重要原因是，没有一个生物标志物可以解释SLE或LN的异质性。在以下假设的假设：多类生物标志物可以代表LN风险的不同方面，我们建议评估分为疾病易感性类别的生物标志物炎症和肾脏室/细胞损伤，以建立风险预测的模型。我们的目标是发展复合生物标志物，用于早期检测肾脏耀斑，慢性肾脏损伤和LN治疗反应患者。为了实现这一目标，我们将使用纵向观察队列和临床的生物测量具有良好的患者样本的试验。南卡罗来纳州医科大学（MUSC）团队因此，建议与俄亥俄州立大学（OSU）团队合作，将每个小组的纵向结合起来 SLE队列并创建了适合生物标志物发现的精心型患者资源，并且足够大充分的电力验证研究。组合的OSU-MUSC队列将有大约500 ln 风湿病/肾脏病诊所就诊和生物测量的患者每两至六个收集的患者最多十年的月份。使用这些样品，我们的集体团队已经描述了几个DNA，与疾病活动，治疗反应或器官损害相关的血清和尿液生物标志物 LN，并且在开发生物标志物面板方面具有丰富的经验。我们已经审查了最近十年的文献，系统地排名新颖的生物标志物，并建议测试表现最高的LN 在此提案中，生物标志物可以解决：（i）与活动LN相关的生物标志物可用于预测前瞻性纵向人群中即将发生的肾脏耀斑；（ii）复合面板的基线测量尿液或血清生物标志物可以区分谁和谁将无法实现对一年的霉酚酸莫菲蒂尔的常规治疗；（iii）发展的遗传风险概况 LN患者可以识别那些易于造成慢性肾脏损伤的患者。我们还将比较生物标志物可预测非肾脏SLE的LN疾病结局，旨在发展LN 特定与一般生物标志物面板，表明有效炎症和/或损害应计。我们的最终目标是验证LN的LN预测指标，具有足够的敏感性和特异性，以使其具有临床相关性，在大多数临床服务实验室中，可以轻松地测定这一点，以改善患者护理。