Acute Kidney Injury in Children with Chronic Kidney Disease

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Project Summary: Acute kidney injury (AKI) is defined as an abrupt loss of kidney function and is very common in children with chronic kidney disease (CKD). AKI is associated with high mortality rates in children and is thought to be a risk factor for a permanent loss of kidney function and development of end stage kidney disease. These elevated risks require urgent focus on AKI in children with CKD to better characterize the modifiable risk factors of AKI as well as understand the relationship between AKI and kidney health. Improving the understanding of the risk factors and pathogenesis of AKI will provide a basis for interventional studies to prevent AKI, limit progression of CKD, and improve long-term outcomes. To study AKI in children with CKD and address a substantial gap in pediatric research, we have developed research studies with the 1100 participants of the CKD in Children (CKiD) cohort, the largest cohort of children with CKD. The yearly study visits with kidney function, blood pressure, and albuminuria measurements for all CKiD participants minimizes the bias and confounding of previous research which retrospectively examined kidney function assessments performed only when clinically indicated. As the kidney tubules are critical to life and essential to supporting multiple critical functions in a growing child, we will conduct a global assessment of kidney health using biomarkers of both glomerular and tubular health. To characterize tubular health including tubular regeneration, injury, dysfunction, and inflammation before and after AKI, we will measure 4 urine biomarkers (epidermal growth factor, kidney injury molecule-1, monocyte chemoattractant protein-1, α-1 microglobulin). They will add substantially to the examination of key pathways that may contribute to CKD progression after AKI. In preliminary data, we observed that after multivariable adjustment, each of these tubular biomarkers is associated with a subsequent decline in kidney function. We also observed at two CKiD sites, that 25 of 83 children (30%) developed at least one episode of AKI and that those with AKI were more than twice as likely to develop CKD progression. The specific aims are: 1) Determine the relationship between characteristics of glomerular and tubular health with the risk of AKI; 2) Determine the association between AKI with the subsequent change of GFR, blood pressure, albuminuria, growth, and tubular health biomarkers; 3) Develop and validate a risk prediction model for future progression of CKD in children combining CKD risk factors, prior AKI characteristics, and biomarkers of tubule health. Our research will represent a foundational epidemiologic study of AKI and may better explain the highly variable long-term outcomes in children with CKD. Completion of our research will provide new insights to identify therapeutic targets and support future interventional studies of AKI in CKD. Furthermore, a validated risk prediction model and understanding of the relationship between AKI and long-term outcomes may provide for the early detection and prompt treatment of GFR decline after AKI.