Cleveland Precision Medicine Chronic Kidney Disease Cohort

克利夫兰精准医学慢性肾脏病队列

• 批准号: 10223909
• 负责人: JOHN F. O'TOOLE
• 金额: $ 30万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223909
• 关键词: APOL1 gene; Address; Adult; Affect; African; African American; Age; American; Automobile Driving; Biological; Biopsy; Blood; Cells; Cessation of life; Chronic Care; Chronic Kidney Failure; Classification; Clinic; Clinical; Clinical Data; Collection; Communities; Computing Methodologies; Consent; Data; Data Discovery; Data Set; Descriptor; Diabetes Mellitus; Diabetic Nephropathy; Diagnosis; Diagnostic radiologic examination; Dialysis procedure; Disease; Disease Outcome; Disease Progression; Electronic Health Record; End stage renal failure; Enrollment; Equation; Ethicists; Ethics; European; Family; Family Physicians; Funding; Gene Expression; Genetic Variation; Genotype; Goals; Health; Histologic; Histology; Human; Hypertension; Image; Implant; Incidence; Individual; Informatics; Informed Consent; Injury to Kidney; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Laboratories; Link; Longterm Follow-up; Magnetic Resonance Imaging; Measurable; Measures; Mediating; Molecular; Molecular Analysis; Monitor; Morphology; Nephrectomy; Ontology; Participant; Pathogenicity; Pathway interactions; Patients; Phase; Phenotype; Population; Probability; Process; Protein Isoforms; Protocols documentation; RNA; RNA Splicing; Radiology Specialty; Research; Research Personnel; Risk; Safety; Sampling; Schedule; Scientist; Site; Slide; Structure; System; Tissue Donors; Tissues; Transcript; United States; Urine; Viral; Visit; Visual; cell type; clinical biomarkers; clinical phenotype; cohort; community partnership; digital imaging; disease phenotype; disorder risk; effective therapy; eligible participant; expectation; follow-up; genetic variant; health care delivery; health disparity; high risk; improved; improved outcome; inclusion criteria; kidney biopsy; kidney imaging; living kidney donor; molecular phenotype; multidisciplinary; new therapeutic target; precision medicine; predictive tools; prospective; recruit; renal damage; repository; satisfaction; standard of care; stool sample; targeted treatment; therapeutic target

Project Abstract Although hypertension is associated with ~25% of end-stage renal disease (H-ESRD) in the United States, the pathogenic mechanisms that drive the initiation and progression of hypertension-associated chronic kidney disease (HTN-CKD) are unclear. The incidence of H-ESRD is 4- to 5-fold greater in African American populations than in whites. To address this health disparity, the Cleveland KPMP Recruiting Network will recruit a cohort of CKD patients with HTN-CKD. Prospective participants with CKD stage 3a will be identified by automated, scheduled queries of the electronic health records (EHR) of two large health care delivery systems in Cleveland, OH, the Cleveland Clinic and MetroHealth. Eligible candidates will be enriched for subjects likely to progress by using the Kidney Failure Risk Equation to identify individuals with > 15% probability of developing ESRD in 5 years. This Network plans enrollment of 10 participants each year during the two year UG3 exploratory phase and 40 to 50 subjects each year for the subsequent, three year UH3 implementation phase. Once kidney research biopsy safety is established in UG3, HTN-CKD subject inclusion criteria in UH3 will be modified to include proteinuric CKD Stage 2 patients. Subjects with other CKD phenotypes can be recruited to support consortium goals. After informed consent, enrolled subjects will undergo a baseline MRI to image kidney structure and a research kidney biopsy and then be followed every 6 months at standard of care visits for the duration of the KPMP. Baseline and longitudinal biosamples will be collected and linked through REDCap to clinical data in the EHRs. The Network plans to obtain additional healthy and disease kidney samples from living donor kidney implant biopsies and an additional tissue core obtained at an indication biopsy from HTN-CKD patients, respectively. Clinical data, biopsy blocks and biosamples will be submitted to Central Hub repositories. The Network includes a Community Partnership Committee composed of CKD patients and families, physicians and an ethicist to guide implementation of this KPMP Network. In anticipation of Opportunity Pool funding, the PIs have recruited co-investigators, who will utilize the rich KPMP molecular, radiologic and histopathologic phenotypes and longitudinal clinical data for discovery. Since excess risk in African Americans for HTN-CKD is largely explained by genetic variations in APOL1, our initial research goal in UH3 is to identify the molecular mechanisms underlying this association. We will integrate molecular and clinical phenotypes with visual and subvisual morphologic descriptors to discover the cells and associated molecular pathways mediating APOL1-associated HTN-CKD. In pilot, proof- of-principle studies, we used computational methods and identified a set of sub-visual morphologic features that discriminated 10 African American kidney transplant implant biopsies with high risk APOL1 genotypes from 6 implant biopsies with low risk APOL1 genotypes. Creative strategies that integrate KPMP datasets will define other research questions to identify biologic pathways driving CKD and result in new CKD therapies.

项目摘要 尽管高血压与美国约25%的终末期肾脏疾病(H-ESRD)有关，但 高血压相关性慢性肾脏发病机制的研究进展 疾病(HTN-CKD)尚不清楚。在非裔美国人中，H-ESRD的发病率要高出4到5倍 在人口中的比例要高于白人。为了解决这一健康差距，克利夫兰KPMP招募网络将 招募一组患有HTN-CKD的CKD患者。CKD阶段3a的潜在参与者将被确定 通过自动、计划地查询两个大型医疗保健服务的电子健康记录(EHR) 在俄亥俄州克利夫兰、克利夫兰诊所和MetroHealth的系统。符合条件的候选人将被充实为 可能进展的受试者使用肾功能衰竭风险方程来识别患有15%肾功能衰竭的个体 未来5年发展终末期肾病的可能性。该网络计划每年招收10名参与者 为期两年的UG3探索阶段，以及随后的三年UH3每年40至50名受试者 实施阶段。一旦肾脏研究活检安全性在UG3、HTN-CKD受试者纳入中确定 UH3的标准将被修改，以包括蛋白尿型CKD 2期患者。患有其他CKD的受试者 表型可以被招募来支持联盟的目标。知情同意后，登记的受试者将 接受基线核磁共振成像以成像肾脏结构，并进行肾脏活检，然后每隔6天进行一次跟踪 在朝鲜民主主义人民共和国淘汰管理计划期间，按标准护理探视数月。基线和纵向生物样本将是 通过RedCap收集并链接到电子病历中的临床数据。该网络计划获得更多 来自活体供肾移植活检的健康和疾病肾脏样本和额外的组织核心 分别从HTN-CKD患者的适应症活检中获得。临床数据，活组织检查块和 生物样本将被提交给中央枢纽储存库。该网络包括一个社区伙伴关系 由CKD患者及其家属、医生和一名伦理学家组成的委员会，以指导该计划的实施 KPMP网络。在预期机会池资金的情况下，投资促进局招募了联合调查员，他们将 利用丰富的KPMP分子、放射学和组织病理学表型和纵向临床数据 发现号。由于非裔美国人患HTN-CKD的过度风险主要是由 APOL1，我们在UH3中的初步研究目标是确定这种联系背后的分子机制。 我们将把分子和临床表型与视觉和视觉下的形态描述符相结合，以 发现介导APOL1相关HTN-CKD的细胞和相关分子通路。在Pilot中，证明- 在原理研究中，我们使用了计算方法，并确定了一组亚视觉形态特征 辨别了10例高危APOL1基因的非裔美国人肾移植活检组织 来自6例低风险APOL1基因的植入活检。整合KPMP数据集的创造性策略将 定义其他研究问题，以确定推动CKD的生物途径，并导致新的CKD疗法。

项目成果

Modelling kidney disease using ontology: insights from the Kidney Precision Medicine Project.

• DOI: 10.1038/s41581-020-00335-w
• 发表时间: 2020-11
• 期刊: Nature reviews. Nephrology
• 作者: Ong E;Wang LL;Schaub J;O'Toole JF;Steck B;Rosenberg AZ;Dowd F;Hansen J;Barisoni L;Jain S;de Boer IH;Valerius MT;Waikar SS;Park C;Crawford DC;Alexandrov T;Anderton CR;Stoeckert C;Weng C;Diehl AD;Mungall CJ;Haendel M;Robinson PN;Himmelfarb J;Iyengar R;Kretzler M;Mooney S;He Y;Kidney Precision Medicine Project
• 通讯作者: Kidney Precision Medicine Project