Abstract Although acute kidney injury (AKI) is common and associated with adverse consequences, no specific AKI therapy has emerged. This has been attributed to the heterogeneity of human AKI, which is poorly modeled by animal experiments. The Kidney Precision Medicine Program (KPMP) was established by the NIH/NIDDK in 2016 to study human kidney tissue during an AKI event in order to discover pathogenic pathways and novel therapeutic targets. The combined Johns Hopkins University (JHU)/Yale University site was funded in the first phase of the KPMP to recruit AKI participants. During this first phase, the JHU/Yale site enrolled over one-half of all AKI participants in KPMP, performed kidney biopsies with a strong commitment to safety and ethics, retained all participants, and played an important role in the initiation and execution of study protocols through committee leadership and participation. Enrollment was successfully restarted after a several-months-long pause in recruitment due to the COVID-19 pandemic, and protocols were established to monitor participant and staff safety. This is an application to continue to serve as an AKI recruitment site for the Kidney Precision Medicine Program (KPMP) to create a high-quality, well-represented resource of tissues and biosamples from hospitalized participants with AKI. The JHU/Yale center’s experience from the first phase of the study will be invaluable as the consortium attempts to increase enrollment in the second phase. The specific aims are: 1) To recruit a total of 150 diverse participants with AKI due to various etiologies and of varying severities in a research study that safely and ethically performs protocol research biopsies to collect kidney tissue and obtain concurrent biosamples and clinical data; 2) to retain participants in a longitudinal study using a hybrid approach of active and passive follow-up that prioritizes participant convenience and obtains high-fidelity follow-up information; and 3) to contribute biosamples from participants with various biopsy-proven etiologies of AKI from larger cohorts with broader enrollment criteria to externally validate KPMP findings. In Aim 1, 30 diverse participants with AKI per year will be enrolled across two academic medical centers while maintaining. high safety and quality standards. In Aim 2, close to 100% follow-up of study participants will be obtained through various approaches to garner information on objective measures of kidney health and patient-reported outcomes. In Aim 3, to provide external validation of the KPMP findings, blood, urine, and DNA from over 500 participants who underwent routine clinically-indicated kidney biopsies for AKI will be contributed to the study. Successful completion of these aims will result in the contribution of kidney tissue, biosamples, and data from participants with AKI to the KPMP consortium to help achieve the broader goal of understanding the pathogenesis of human AKI. This will lead to the identi...