Project Summary Pediatric chronic kidney disease (pCKD) is most commonly due to congenital anomalies of the kidney and urinary tract; thus, meaning a lifetime of disease. Children with even mild CKD are at risk for neurocognitive difficulties specific to attention regulation, academic underachievement, and executive function [1-3]. Neurocognitive deficits have broad implication on quality of life, as they contribute to poorer high school graduation rates and long-term underemployment in the adult CKD population [4]. The cognitive complications of pCKD are thought to represent sequelae of an aberrant “kidney-brain axis” whereby kidney impairment and associated disease sequelae may negatively impact the brain, leading to increased risk of cognitive impairment in the course of pCKD progression [5-7]. However, there is a critical gap in our understanding of the developing brain in the context of pCKD. Thus, the overarching goal of this proposal is to quantify structural and functional brain differences using MRI and cognitive/behavioral assessments in pCKD participants with mild to moderate (early) CKD compared to unaffected controls. To our knowledge, this proposal is the first in the world to quantitatively evaluate the brain in young children with early stage pCKD due to a focused disease etiology using magnetic resonance imaging (MRI). Preliminary data from our laboratory are striking and demonstrate robust structural brain differences (particularly within the cerebellum) in children with congenital, non-glomerular causes of CKD compared to healthy peers. There appears to be a direct relationship between decreased cerebellum volume and impaired kidney function. Furthermore, lower cerebellum gray matter volume appears to predict performance on neurocognitive tasks specific to executive function in children with CKD. Our pilot data demonstrate abnormal resting state connectivity in pCKD whereby children with CKD show hypo-connectivity between the cerebellum (dentate nucleus) and the frontal cortices. We will investigate a “dosage” effect of disease burden on neurodevelopment in children with mild/moderate CKD. Understanding the influence of pCKD progression and severity on the developing brain will allow enhanced awareness of the role of disease progression on neurodevelopmental outcomes in childhood and inform new approaches to patient care across the CKD lifespan.