Cleveland Precision Medicine Chronic Kidney Disease Cohort

项目摘要 尽管在美国，高血压与约25%的终末期肾病（H-ESRD）相关， 驱动高血压相关慢性肾脏病发生和发展的致病机制 HTN-CKD的病因尚不清楚。在非裔美国人中，H-ESRD的发病率高4- 5倍 人口比白人多。为了解决这种健康差距，克利夫兰KPMP招聘网络将 招募一组患有HTN-CKD的CKD患者。将确定CKD 3a期的前瞻性受试者 通过对两个大型医疗保健机构的电子健康记录（EHR）进行自动化、计划化查询， 系统在克利夫兰，俄亥俄州，克利夫兰诊所和大都会健康。符合条件的候选人将得到丰富， 受试者可能通过使用肾衰竭风险方程来确定> 15%的个体 5年内发生ESRD的可能性。该网络计划每年招收10名参与者， 2年UG 3探索期，随后3年UH 3每年40 - 50例受试者 实施阶段。一旦在UG 3中确定了肾脏研究活检安全性，HTN-CKD受试者入选 UH 3中的标准将被修改以包括蛋白尿CKD 2期患者。其他CKD受试者 表型可以被招募来支持联合体的目标。知情同意后，入组受试者将 进行基线MRI以成像肾脏结构和研究肾脏活检，然后每6 在KPMP持续期间，标准护理访视时为3个月。基线和纵向生物样本将 通过REDCap收集并链接到EHR中的临床数据。该网络计划获得更多的 来自活体供体肾移植物活组织检查的健康和患病肾样品以及额外的组织芯 分别从HTN-CKD患者的适应症活检中获得。临床数据、活检组织块和 生物样本将被提交至中央枢纽储存库。该网络包括一个社区伙伴关系 由CKD患者和家属、医生和伦理学家组成的委员会，指导实施本 KPMP Network.在机会池资金的预期下，PI已经招募了共同调查员，他们将 利用丰富的KPMP分子、放射学和组织病理学表型以及纵向临床数据， 的发现由于非裔美国人患HTN-CKD的过度风险在很大程度上是由遗传变异引起的， APOL 1，我们在UH 3中的初步研究目标是确定这种关联的分子机制。 我们将整合分子和临床表型与视觉和亚视觉形态描述符， 发现介导APOL 1相关HTN-CKD的细胞和相关分子通路。在试点，证明- 原则的研究，我们使用计算方法，并确定了一组亚视觉形态特征 区分10例具有高风险APOL 1基因型的非裔美国人肾移植植入物活检， 来自6个具有低风险APOL 1基因型的植入物活检。整合KPMP数据集的创造性策略将 定义其他研究问题，以确定驱动CKD的生物学途径，并导致新的CKD疗法。

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.