Cleveland Precision Medicine Chronic Kidney Disease Cohort

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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.