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

• 批准号: 10398139
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398139
• 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; Interferon-alpha; 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

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.

项目摘要/摘要 丙型肝炎病毒（HCV）感染是慢性肾脏疾病（CKD）的常见合并症 导致加速发展为末期肾脏疾病。由于最近获得了全部批准， 干扰素（IFN） - 无直接作用抗病毒疗法（DAAS），HCV现在可以治愈大多数人 治疗。该建议旨在确定确定由DAA治疗的患者的CKD结局的因素， 并研究消除HCV后发生的IFN激活对肾脏功能的影响。 AIM 1使用学习医疗系统（SCILHS）网络的可扩展协作基础架构， 一个涵盖12个医疗保健系统的电子健康记录网络，以检查大型，多样的队列 10,000例HCV感染对（1）确定DAA对EGFR下降的影响五年后的影响 - UP和（2）确定预测哪些HCV感染患者的因素，尽管 HCV感染的治疗。 AIM 2A建议招募40名HCV和CKD患者接受DAA 前瞻性研究IFN-Pathway的治疗方法，以确定单核细胞化学吸引蛋白1（MCP-1）， IFN激活的候选标志物预测哪些患者将具有进行性CKD，哪些将恢复。 AIM 2B检查患有从免疫介导的肾脏疾病（类似狼疮的免疫）的患者 DAA后，复杂的肾小球肾炎和局灶性节段性肾小球硬化）确定基线和基线是否是否 在自身免疫性的患者中，治疗后IFN刺激的基因和趋化因子增加。 这项K23指导了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博士做好准备工作 独立的学术医学转化研究员。 Sise博士的临床培训是内科 和肾脏科，并在生物统计学和以患者为导向的研究中进行了先前的硕士学位培训。在 她的机构将为她提供75％的时间来支持她的职业发展奖。 专注于制定该研究计划并完成纵向数据中的教学和实践培训 分析和免疫学通过课程和应用分析经验。 Sise博士将从 她的主要导师的指导，基本，翻译和国际领导者Raymond Chung博士 HCV和HIV的临床研究，以及她的同事Ravi Thadhani博士，已建立的临床和转化 CKD调查员。她的培训还将受到高级科学家Drs的咨询委员会的监督。朱尔斯 Dienstag，Steven Grinspoon和Arthur Kim，具有免疫激活机制的集体专业知识 HCV和HIV，生物标志物研究和临床试验。她将与肯尼斯·曼德尔（Kenneth Mandl）博士合作 （Scilhs Network Pi），Sushrut Waikar博士（CKD生物标志物）和Y​​uchiao Chang博士（统计学家）。 Sise博士 目标是通过研究计划成为学术中心的独立临床医生评估者 专注于减慢CKD进展的策略。

项目成果

Filter clotting with continuous renal replacement therapy in COVID-19.

• DOI: 10.1007/s11239-020-02301-6
• 发表时间: 2021-05
• 期刊: Journal of thrombosis and thrombolysis
• 影响因子: 4
• 作者: Endres P;Rosovsky R;Zhao S;Krinsky S;Percy S;Kamal O;Roberts RJ;Lopez N;Sise ME;Steele DJR;Lundquist AL;Rhee EP;Hibbert KA;Hardin CC;Mc Causland FR;Czarnecki PG;Mutter W;Tolkoff-Rubin N;Allegretti AS
• 通讯作者: Allegretti AS

Safety and Efficacy of Immune Checkpoint Inhibitors in Patients on Dialysis: A Retrospective Case Series.

• DOI: 10.1053/j.ajkd.2020.02.451
• 发表时间: 2020-08
• 期刊: American journal of kidney diseases : the official journal of the National Kidney Foundation
• 作者: Strohbehn IA;Lee M;Seethapathy H;Chute D;Rahma O;Guidon A;Neilan TG;Zlotoff DA;Okin D;Rengarajan M;Reynolds K;Sise ME
• 通讯作者: Sise ME

Medication-Related Adverse Events and Discordancies in Cystatin C-Based vs Serum Creatinine-Based Estimated Glomerular Filtration Rate in Patients With Cancer.

• DOI: 10.1001/jamanetworkopen.2023.21715
• 发表时间: 2023-07-03
• 期刊: JAMA NETWORK OPEN
• 影响因子: 13.8
• 作者: Hanna, Paul E.;Wang, Qiyu;Strohbehn, Ian A.;Moreno, Daiana;Harden, Destiny;Ouyang, Tianqi;Katz-Agranov, Nurit;Seethapathy, Harish;Reynolds, Kerry L.;Gupta, Shruti;Leaf, David E.;Sise, Meghan E.
• 通讯作者: Sise, Meghan E.

Acute Kidney Injury Following Encorafenib and Binimetinib for Metastatic Melanoma.

恩科拉非尼和比尼美替尼治疗转移性黑色素瘤后的急性肾损伤。

• DOI: 10.1016/j.xkme.2020.01.012
• 发表时间: 2020
• 期刊: Kidney medicine
• 影响因子: 3.9
• 作者: Seethapathy,Harish;Bates,Halla;Chute,DonaldF;Strohbehn,Ian;Strohbehn,Samuel;Fadden,RileyM;Reynolds,KerryL;Cohen,JustineV;Sullivan,RyanJ;Sise,MeghanE
• 通讯作者: Sise,MeghanE

Acute kidney injury after ruxolitinib: Common complication, uncommon cause.

• DOI: 10.1002/ajh.25804
• 发表时间: 2020-07
• 期刊: American journal of hematology
• 影响因子: 12.8
• 作者: Strohbehn S;Seethapathy H;Rusibamayila N;Strohbehn I;Lee M;Hobbs G;Keyzner A;Jhaveri KD;Sise ME
• 通讯作者: Sise ME