ABSTRACT The overall incidence of acute kidney injury (AKI) is estimated to be about 2-3/1000 US population, similar to that of acute myocardial infarction. However, because of the silent nature of the syndrome, this is likely an underestimate. Older individuals are disproportionately affected. Among Medicare patients age 66–69, for example, the rate of AKI in 2011 was 14.9 per 1,000 patients, increasing to 18.8, 26.4, 35.9, and 49.6 respectively for ages 70–74, 75–79, 80–84, and 85 and older. This same demographic relationship also exists for many causes of AKI such as sepsis and cardiac surgery, the two leading causes of AKI. Recent evidence suggests that much milder forms of AKI are also associated with increased risk of hospital mortality. Although the reasons for this increased mortality are not fully understood, these studies and many others make a compelling argument that patients who develop AKI are at an additional increased risk of death that is in some way due to AKI itself. Relatively little is known about the underlying mechanisms of AKI in humans and much has been written about the limitations of experimental models; the scientific foundation for AKI is weak and tissue from early AKI is virtually nonexistent. Our current understanding is that long-term outcomes are linked to development of chronic kidney disease (CKD). Thus exists a critical need for longitudinal epidemiologic studies linked to biologic samples (tissue, blood and urine) that would allow the testing of multiple hypotheses as to the nature of this disease and its pathophysiology. Prior interventions for the treatment of AKI have failed due to our basic lack of understanding; greater understanding of the pathophysiology of AKI will permit development of new interventions. This application, PReCISE AKI (Phenotyping REnal Cases In Sepsis and surgery for Early Acute Kidney Injury), will leverage six strengths of our recruitment site: 1. An established AKI alerting system within the electronic medical record (EMR) standardized across 14 hospitals in western Pennsylvania; 2. Biomarkers for early identification of AKI; 3. Established research and clinical collaboration across medical, surgical and emergency medicine services, specifically for AKI; 4. Existing studies for patient accrual and long-term follow- up in AKI; 5. Extensive experience with biobanking including blood and urine samples; 6. A program for protocolized kidney biopsies for a large kidney transplant program. We note that some of these strengths are unique—particularly, the use of novel biomarker enrichment and enrollment of surgical patients with intraoperative biopsies. Using these strengths, we aim to obtain biopsies from patients with a range of AKI syndromes in a safe and ethical manner, test the hypothesis that specific clinical phenotypes of AKI have differing biopsy findings and then compare adjudicated etiology of AKI to biopsy results and to clinical outcomes; and determine whether biopsy findings can predict early resolution and subsequent risk for CKD.

PROJECT NARRATIVE AKI is as common as myocardial infarction in the western countries, but it is silent and is associated with a high rate of poor outcome and death. The scientific foundation for AKI is weak and tissue from early AKI is virtually nonexistent; thus remains a critical need for studies of biologic samples (biopsy tissue, blood and urine) that would allow the testing of multiple hypotheses as to the nature of this disease permitting development of new treatments. PReCISE AKI (Phenotyping REnal Cases In Sepsis and surgery for Early Acute Kidney Injury) will enroll patients with early acute kidney injury (AKI) as well as patients with established AKI, obtain biopsies from patients with a range of AKI syndromes in a safe and ethical manner, test the hypothesis that specific clinical phenotypes of AKI have different biopsy findings, and determine whether biopsy findings can predict early resolution and subsequent risk for chronic kidney disease.