Effect of Hepatitis C Virus Eradication on Chronic Kidney Disease Progression

项目摘要/摘要 丙型肝炎病毒(丙型肝炎病毒)感染是慢性肾脏病(CKD)患者的常见共病 导致加速进展为终末期肾病。由于最近全口服药的批准， 不含干扰素(干扰素)的直接作用抗病毒疗法(DAAs)，丙型肝炎病毒现在可以在大多数人中治愈 治疗过了。这项建议旨在确定决定接受DAA治疗的患者CKD结局的因素， 并探讨丙型肝炎病毒根除后干扰素活性增强对肾功能的影响。 AIM 1采用面向学习型医疗保健系统(SCILHS)网络的可扩展协作基础设施， 覆盖12个医疗保健系统的电子健康记录网络，以检查大量不同的 10,000名丙型肝炎病毒感染患者将(1)确定DAAs对五年内EGFR下降的影响-- UP和(2)确定预测哪些丙型肝炎感染患者可能患有进展性CKD的因素 丙型肝炎病毒感染的治疗。Aim 2A建议招募40名接受DAA治疗的丙型肝炎和慢性肾脏病患者 前瞻性研究干扰素途径以确定单核细胞趋化蛋白1(MCP-1)、 干扰素激活的候选标志物，预测哪些患者将患有进展性CKD，哪些将恢复。 目的2B检查新发免疫介导性肾脏疾病(狼疮样免疫)患者 复杂肾小球肾炎和局灶节段性肾小球硬化) 治疗后，自身免疫患者的干扰素刺激基因和趋化因子会增加。 这份K23指导的以患者为导向的研究职业发展奖提案旨在探索 根除丙型肝炎和激活干扰素对慢性肾脏病进展的影响，并为赛斯博士的职业生涯做好准备 学术医学领域的独立翻译研究员。赛斯医生的临床训练是在内科 和肾脏学，在生物统计学和以患者为导向的研究方面接受过硕士水平的培训。在.期间 在这个职业发展奖的过程中，她将得到她所在机构的支持，将75%的时间投入到 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 通过课程工作和应用分析经验掌握分析和免疫学。塞斯博士将受益于 她的主要导师雷蒙德·钟博士的指导，他是基础、翻译和 丙型肝炎病毒和艾滋病毒的临床研究，以及她的合作导师拉维·塔哈尼博士，一位公认的临床和翻译人员 CKD调查员。她的培训还将由资深科学家朱尔斯博士组成的咨询委员会监督 Dienstag，Steven Grincoon和Arthur Kim，在免疫激活机制方面的集体专业知识 丙型肝炎病毒和艾滋病毒、生物标记物研究和临床试验。她将与肯尼斯·曼德尔博士合作 (SCILHS Network Pi)、Sushrut Waikar博士(CKD生物标志物)和张玉桥博士(Statistician)。塞斯医生的 目标是成为一名拥有研究计划的学术中心的独立临床医生兼研究员 专注于减缓慢性肾脏病进展的策略。

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.