Pediatric CKD Linked to Abnormal Cerebellar Growth, Executive Dysfunction

Lyndsay Harshman, MD

Credit: Iowa Health Care

New research is shedding light on age-related neurodevelopmental differences in pediatric patients with chronic kidney disease (CKD) compared with healthy peers.¹

Findings from the case-control study highlight abnormal growth trajectories of the cerebellum in patients with CKD, additionally suggesting abnormal cerebellum gray matter is associated with executive dysfunction and lower kidney function.¹

“Until recently, the neurobiology of cognitive deficits in pediatric CKD was largely uncharacterized. This work extends prior findings using a larger sample encompassing young adulthood,” Lyndsay Harshman, MD, an associate professor of pediatric nephrology, dialysis and transplantation and medical director of pediatric kidney transplant at the University of Iowa Carver College of Medicine, and colleagues wrote.¹ “It is the first study we know of in CKD literature to explicitly characterize age-related neurodevelopmental changes associated with CKD.”

According to the US Centers for Disease Control and Prevention, more than 1 in 7 US adults—about 35.5 million people—are estimated to have CKD. It is more common in people ≥ 65 years of age (34%) than in people 45–64 years of age (12%) or 18–44 years of age (6%).² In children, about half of CKD diagnoses are due to congenital anomalies of the kidney and urinary tract, and their decline in kidney function is thought to have significant neurocognitive and neurodevelopmental implications.¹

To explore age-related neurodevelopmental trajectories in adolescent and young adult patients with CKD, investigators examined electronic medical record data for patients with CKD seen at the University of Iowa from September 2016 through August 2024. Those with extreme prematurity (<30 weeks’ gestational age); seizures and/or receipt of antiepileptic medications; central nervous system anomalies; congenital cardiac disease; diagnosed intellectual disability; traumatic brain injury requiring hospitalization; and/or magnetic resonance imaging contraindications, were excluded from the analysis.¹

Investigators additionally recruited unaffected individuals from the local community through advertisements with intent to align controls with participants with CKD based on age, sex, and maternal education.¹

Participants completed age-appropriate, standardized neurocognitive assessments with a focus on executive functioning, which were administered by trained examiners and supervised by a licensed psychologist. Participants also completed a nonsedated, non-contrast-enhanced MRI of the brain, and investigators estimated their kidney function from blood samples using the combined creatinine-cystatin C CKiD U25 equation.¹

In total, the study included 124 individuals 6-21 years of age, including 87 control participants and 37 participants with CKD. Investigators noted participants with CKD scored lower than control participants on most neurocognitive measures included in the analyses.¹

The CKD group showed differential age-related changes in cerebellar gray matter (β = −0.10; 95% CI, −0.18 to −0.01; Cohen f = 0.22) and white matter (β = −0.09; 95% CI, −0.19 to −0.00; Cohen f = 0.19). For amygdala volume, the age and group interaction approached but did not reach significance (β = 0.09; 95% CI, −0.01 to 0.19; Cohen f = 0.18; P = .06).¹

Further analysis revealed cerebellum gray matter was associated with planning/organization (β = 0.55; 95% CI, 0.04 to 1.10; P = 04), cerebellum white matter was associated with emotional control (β = 0.42; 95% CI, 0.02 to 0.82; P = 04), and amygdala volume was associated with monitor (β = −0.40; 95% CI, −0.76 to −0.04; P <.03). Investigators noted the cerebellum white matter and emotional control association was due to an outlier, as the regression coefficient for cerebellum white matter did not reach significance when this observation was removed (β = 0.48; 95% CI, −0.04 to 1.00; P = .07).¹

In the CKD croup, investigators called attention to a significant positive association between cerebellar gray matter and eGFR (eGFR β = 0.01; 95% CI, 0.00 to 0.02; P = .01), but not cerebellum white matter (eGFR β = 0.00; 95% CI, −0.01 to 0.02) or amygdala volume (eGFR β = 0.00; 95% CI, −0.11 to 0.02). Of note, the association between eGFR and the superior posterior lobe of the cerebellum reached significance (eGFR β = 0.02; 95% CI, 0.01 to 0.03; P = .001).¹

“Our findings suggested that reduced cerebellum volume was associated with both lower kidney function and EF deficits,” investigators concluded.¹ “This is the first study we know of in the CKD literature to explicitly characterize age-related neurodevelopmental changes associated with CKD.”

References

1. ^{van der Plas E, Nelson E, Becknell B, et al. Age-Related Changes in Brain Structure in Pediatric Chronic Kidney Disease. JAMA Network Open. doi:10.1001/jamanetworkopen.2024.57601}
2. ^{US Centers for Disease Control and Prevention. Chronic Kidney Disease in the United States, 2023. Accessed February 3, 2025. https://www.cdc.gov/kidney-disease/php/data-research/index.html}