Effect of Hepatitis C Virus Eradication on Chronic Kidney Disease Progression

根除丙型肝炎病毒对慢性肾脏病进展的影响

基本信息

批准号：
10159102
负责人：
Meghan E. Sise
金额：
$ 17.26万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2018-07-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10159102
关键词：
Adult Advisory Committees Affect Aftercare Antiviral Agents Antiviral Therapy Autoimmunity Biological Markers Biometry CCL1 gene CCL2 gene CXCL10 gene Chronic Chronic Kidney Failure Clinical Clinical Research Clinical Trials Collaborations Data Data Analyses Development Disease Outcome Disease Progression Educational Status Electronic Health Record End stage renal failure Enrollment Epidemiology Failure Focal Segmental Glomerulosclerosis Funding Gene Activation Genes Glomerular Filtration Rate Glomerulonephritis Goals HIV Healthcare Systems Hepatitis C Hepatitis C Therapy Hepatitis C virus Immune Immune Complex Glomerulonephritis Immunologics Immunology Incidence Inflammatory Infrastructure Institution Interferon Activation Interferons Interleukin-18 Internal Medicine International K-Series Research Career Programs Kidney Kidney Diseases Knowledge LCN2 gene Lead Learning Logistic Regressions Measures Mediating Medicine Mentored Patient-Oriented Research Career Development Award Mentors Mentorship Nephrology Oral Organ Outcome Pathway interactions Patients Peripheral Blood Mononuclear Cell Plasma Population Positioning Attribute Predictive Factor Prospective Studies Proteinuria Recovery Renal function Research Research Personnel Risk Role Sampling Senior Scientist Syndrome Testing Time Training United States United States National Institutes of Health Viral Virus Diseases Work anti-hepatitis C base candidate marker career chemokine chronic infection cohort comorbidity diabetic effective therapy experience follow-up immune activation immune reconstitution improved liver transplantation longitudinal analysis lupus-like novel novel therapeutic intervention patient oriented research patient subsets programs prospective recruit repository response secondary analysis skills success translational approach translational scientist translational study urinary

项目摘要

PROJECT SUMMARY/ABSTRACT Hepatitis C Virus (HCV) infection is a common comorbidity in patients with chronic kidney disease (CKD) that leads to accelerated progression to end-stage renal disease. Because of the recent approval of all-oral, interferon (IFN)-free, direct-acting antiviral therapy (DAAs), HCV can now be cured in the majority who are treated. This proposal seeks to identify factors that determine CKD outcomes in patients treated with DAAs, and to investigate the effect of enhanced IFN activation that occurs after HCV eradication on kidney function. Aim 1 employs the Scalable Collaborative Infrastructure for a Learning Healthcare System (SCILHS) Network, an electronic health records network covering 12 healthcare systems, to examine a large, diverse cohort of 10,000 patients with HCV infection to (1) determine the effect of DAAs on eGFR decline over five years follow- up and (2) identify factors that predict which HCV-infected patients are likely to have progressive CKD despite treatment of HCV infection. Aim 2A proposes to recruit 40 patients with HCV and CKD undergoing DAA treatment to prospectively study the IFN-pathway to determine if monocyte chemoattractant protein 1 (MCP-1), a candidate marker of IFN-activation, predicts which patients will have progressive CKD and which will recover. Aim 2B examines patients who develop de novo immune-mediated kidney diseases (lupus-like immune complex glomerulonephritis and focal segmental glomerulosclerosis) after DAAs to determine if baseline and post-treatment IFN-stimulated genes and chemokines are increased in patients who develop autoimmunity. This K23 Mentored Patient-Oriented Research Career Development Award proposal seeks to explore the effect of HCV eradication and IFN activation on CKD progression, and to prepare Dr. Sise for a career as an independent translational researcher in academic medicine. Dr. Sise's clinical training is in internal medicine and nephrology, with prior Masters-level training in biostatistics and patient-oriented research. During the course of this career development award, she will be supported by her institution to devote 75% of her time to focus on developing this research plan and completing didactic and hands-on training in longitudinal data analysis and immunology through coursework and applied analytic experience. Dr. Sise will benefit from the guidance of her primary mentor, Dr. Raymond Chung, an international leader in basic, translational, and clinical studies of HCV and HIV, and her co-mentor Dr. Ravi Thadhani, an established clinical and translational CKD investigator. Her training will also be overseen by an advisory committee of senior scientists, Drs. Jules Dienstag, Steven Grinspoon, and Arthur Kim, with collective expertise in mechanisms of immune activation in HCV and HIV, biomarker research, and clinical trials. She will work in collaboration with Dr. Kenneth Mandl (SCILHS network PI), Dr. Sushrut Waikar (CKD biomarkers) and Dr. Yuchiao Chang (Statistician). Dr. Sise's goal is to become an independent clinician-investigator at an academic center with a research program focused on strategies to slow CKD progression.

项目概要/摘要丙型肝炎病毒 (HCV) 感染是慢性肾脏病 (CKD) 患者的常见合并症，导致加速进展为终末期肾病。由于最近批准了全口头，通过无干扰素 (IFN) 的直接作用抗病毒治疗 (DAA)，大多数 HCV 患者现在可以治愈治疗。该提案旨在确定决定接受 DAA 治疗的患者 CKD 结局的因素，并研究 HCV 根除后 IFN 激活增强对肾功能的影响。目标 1 采用可扩展协作基础设施用于学习医疗保健系统 (SCILHS) 网络，覆盖 12 个医疗保健系统的电子健康记录网络，用于检查大量不同的人群 10,000 名 HCV 感染患者 (1) 确定 DAA 在五年内对 eGFR 下降的影响 (2) 确定预测哪些 HCV 感染患者可能患有进行性 CKD 的因素，尽管 HCV 感染的治疗。目标 2A 建议招募 40 名接受 DAA 的 HCV 和 CKD 患者前瞻性研究 IFN 通路的治疗以确定单核细胞趋化蛋白 1 (MCP-1) 是否 IFN 激活的候选标志物，可预测哪些患者将患有进展性 CKD，哪些患者将会康复。目标 2B 检查患有从头免疫介导的肾脏疾病（狼疮样免疫）的患者 DAA 后确定基线和发生自身免疫的患者治疗后 IFN 刺激的基因和趋化因子增加。这项 K23 指导的以患者为导向的研究职业发展奖提案旨在探索 HCV 根除和 IFN 激活对 CKD 进展的影响，并为 Sise 博士的职业生涯做好准备学术医学领域的独立转化研究员。 Sise 医生的临床培训是内科和肾脏病学，之前接受过生物统计学和以患者为导向的研究方面的硕士学位培训。期间在获得该职业发展奖的过程中，她将得到所在机构的支持，投入75%的时间专注于制定本研究计划并完成纵向数据的教学和实践培训通过课程作业和应用分析经验来学习分析和免疫学。 Sise 博士将受益于她的主要导师 Raymond Chung 博士是基础、转化和应用领域的国际领导者。 HCV 和 HIV 的临床研究，以及她的共同导师 Ravi Thadhani 博士，一位知名的临床和转化专家 CKD 调查员。她的培训还将由资深科学家顾问委员会监督。朱尔斯 Dienstag、Steven Grinspoon 和 Arthur Kim 在免疫激活机制方面拥有集体专业知识 HCV 和 HIV、生物标志物研究和临床试验。她将与 Kenneth Mandl 博士合作（SCILHS 网络 PI）、Sushrut Waikar 博士（CKD 生物标志物）和 Yuchoo Chang 博士（统计学家）。西斯博士的目标是成为具有研究项目的学术中心的独立临床医生研究员重点关注减缓 CKD 进展的策略。