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.

项目总结/摘要 丙型肝炎病毒（HCV）感染是慢性肾病（CKD）患者的常见合并症， 导致加速进展为终末期肾病。由于最近批准的所有口头， 干扰素（IFN）免费，直接作用的抗病毒治疗（DAA），HCV现在可以治愈大多数谁是 治疗。该提案旨在确定DAA治疗患者中决定CKD结局的因素， 并研究HCV根除后IFN活化增强对肾功能的影响。 目标1采用可扩展的协作基础设施学习医疗保健系统（SCILHS）网络， 一个覆盖12个医疗保健系统的电子健康记录网络，以检查一个庞大的，多样化的队列， 10，000例HCV感染患者，以（1）确定DAA对5年内eGFR下降的影响- （2）确定预测HCV感染患者可能患有进展性CKD的因素， 治疗HCV感染。目的2A拟招募40例接受DAA的HCV和CKD患者 治疗以前瞻性地研究IFN-途径以确定单核细胞趋化蛋白1（MCP-1）， IFN-活化的候选标志物，预测哪些患者将患有进展性CKD，哪些患者将康复。 目的2B检查新发免疫介导的肾病（狼疮样免疫性肾病）患者， 复杂性肾小球肾炎和局灶节段性肾小球硬化），以确定基线和 治疗后IFN-刺激的基因和趋化因子在发生自身免疫的患者中增加。 这个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博士的职业生涯做准备， 学术医学的独立翻译研究员。Sise医生的临床训练是内科 和肾脏病学，在生物统计学和以病人为导向的研究之前的硕士水平的培训。期间 在获得职业发展奖的过程中，她将得到所在机构的支持，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 分析和免疫学通过课程和应用分析经验。Sise博士将受益于 她的主要导师，雷蒙德钟博士，在基础，翻译， HCV和HIV的临床研究，以及她的共同导师Ravi Thadhani博士，一位成熟的临床和翻译 CKD研究者。她的训练也将由资深科学家组成的咨询委员会监督， Dienstag，Steven Grinspoon和亚瑟金，在免疫激活机制方面具有集体专业知识， HCV和HIV，生物标志物研究和临床试验。她将与肯尼斯·曼德尔博士合作 （SCILHS网络PI），Sushrut Waikar博士（CKD生物标志物）和Yuchiao Chang博士（Staucian）。Sise博士的 我的目标是成为一名独立的临床研究员，在一个有研究项目的学术中心工作 专注于减缓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

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

Rapid corticosteroid taper versus standard of care for immune checkpoint inhibitor induced nephritis: a single-center retrospective cohort study.

• DOI: 10.1136/jitc-2020-002292
• 发表时间: 2021-04
• 期刊: Journal for immunotherapy of cancer
• 影响因子: 10.9
• 作者: Lee MD;Seethapathy H;Strohbehn IA;Zhao SH;Boland GM;Fadden R;Sullivan R;Reynolds KL;Sise ME
• 通讯作者: Sise ME

A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant.

• DOI: 10.1016/j.kint.2020.12.015
• 发表时间: 2021-07
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Murakami N;Mulvaney P;Danesh M;Abudayyeh A;Diab A;Abdel-Wahab N;Abdelrahim M;Khairallah P;Shirazian S;Kukla A;Owoyemi IO;Alhamad T;Husami S;Menon M;Santeusanio A;Blosser CD;Zuniga SC;Soler MJ;Moreso F;Mithani Z;Ortiz-Melo D;Jaimes EA;Gutgarts V;Lum E;Danovitch GM;Cardarelli F;Drews RE;Bassil C;Swank JL;Westphal S;Mannon RB;Shirai K;Kitchlu A;Ong S;Machado SM;Mothi SS;Ott PA;Rahma O;Hodi FS;Sise ME;Gupta S;Leaf DE;Devoe CE;Wanchoo R;Nair VV;Schmults CD;Hanna GJ;Sprangers B;Riella LV;Jhaveri KD;Immune Checkpoint Inhibitors in Solid Organ Transplant Consortium
• 通讯作者: Immune Checkpoint Inhibitors in Solid Organ Transplant Consortium