Impact of Pediatric CKD on Neurobiology and Brain Iron Deposition

Background: Pediatric chronic kidney disease (CKD) is associated with various systemic complications, including neurodevelopmental deficits and disturbances in iron metabolism. Our previous studies in children with CKD found increases in brain iron deposition by T2*-weighted magnetic resonance imaging (MRI). Excess iron accumulation can lead to oxidative damage in neurons and may be a key mediator of neurobehavioral deficits. However, no in vivo studies have recapitulated this “kidney-brain” phenotype and investigated the association between brain iron metabolism and behavioral outcomes.

Objectives: To investigate the impact of CKD-induced iron dysregulation on neurodevelopment

Design/Methods: Renal hypoplasia mice (Tg(Meox1-nucTagRFP), n=9) and controls (n=8) underwent brain MRI on a small animal 7T scanner at 10 weeks. T2* MRI maps were conducted using median filter and curve fitting with four acquired T2*-weighted echoes. Image processing was performed with the Functional MRI of the Brain Diffusion toolbox. Locomotor activity was assessed by rotarod and open field tests (OFT). Brain tissues were harvested for neuropathology and Perls Prussian blue iron staining. Unpaired t-tests analyzed group differences and linear regression models were utilized to assess the impact of brain iron deposition and behavioral outcomes.

Results: Blood urea nitrogen levels were increased in mice with CKD compared to control (p < 0.05). In CKD mice, shorter T2* relaxation time was associated with increased global and cerebellar iron deposition (p < 0.05) with differences primarily driven by iron deposits in gray matter (p < 0.05). Mice with CKD had significantly shorter total distances traveled in the OFT and rotarod (p < 0.05). Shorter rotarod distance was significantly associated with increased iron deposition in the cerebellum (R2=0.88, p< 0.05). Post-mortem histology also showed significantly higher positive Prussian blue staining in the brain (p < 0.05) and thinner cerebellar granular layers on neuropathology (p < 0.05) compared to controls.

Conclusions: CKD is associated with significant deviations in neurobiology including increased brain iron deposition by MRI, decreased locomotor activity, and abnormal cerebellar neuropathology. Increased iron deposition in the cerebellum predicted worsening locomotor outcomes. The results of this in vivo study correlate with MRI data previously seen in children and provide an opportunity to further investigate the mechanism of abnormal iron metabolism on brain development in pediatric CKD.