Cognitive Profiles and Neuroimaging Correlates in Mild to Moderate Pediatric Chronic Kidney Disease

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Project Summary/Abstract The purpose of this Mentored Patient-Oriented Research Career Development Award (K23) application is to support my short-term career objective of quantitatively characterizing brain structure and function in children with mild to moderate chronic kidney disease (CKD) using magnetic resonance imaging (MRI). Over 50% of all cases of pediatric CKD are due to congenital (structural) anomalies, and as such, the diagnosis portends a life- long diagnosis requiring routine care. Features of renal decline in pediatric CKD include metabolic acidosis, cardiovascular disease, poor growth, and anemia—all of which may have a deleterious, multifactorial impact on the developing brain. It is a natural extension that children with advanced CKD are at risk for neurocognitive decline. Specifically, despite generally intact intelligence (IQ), children with CKD demonstrate deficits in executive function and academic achievement. Neuroimaging research has utilized heterogenous samples (including end-stage renal disease) with reliance on computerized tomography. No published pediatric studies have applied quantitative structural or functional neuroimaging techniques. We will quantify structural and white matter brain differences using MRI in pediatric CKD patients with mild to moderate, non-glomerular CKD compared to healthy controls; it will be the first study to utilize functional MRI sequences to characterize brain pH as a proxy of CKD-related metabolic disease. The study will use neurocognitive and laboratory assessment in conjunction with neuroimaging correlates of brain structure and function in the pediatric CKD population. Our hypotheses, based on preliminary data, predict volumetric and white matter differences will be observed in the cerebellums of CKD participants. These differences will involve integral cortico-thalamic-cerebellar white matter tracts associated with executive function. We will investigate a “dosage” effect of disease burden on cerebellar volume and white matter development by evaluating a cross-sectional cohort of children with mild to moderate CKD in comparison to healthy controls. Understanding the influence of pediatric CKD progression and severity on the developing brain will allow enhanced awareness of the role of disease progression, specifically metabolic disease, on neurodevelopmental outcomes in childhood and inform new approaches to treatment and patient education across the CKD lifespan. My clinical work in pediatric nephrology and introductory work with neuroimaging have laid a solid foundation for achieving these goals. Further training is necessary in sophisticated neuroimaging methods, neurodevelopment, and statistics. The proposed integrated research, mentorship, and didactic training programs, combined with the outstanding research environment at the University of Iowa and off-site mentorship from faculty at Children's Hospital of Philadelphia, will foster my long-term career objective to be an independent investigator studying brain structure and function in pediatric CKD.