Neurocognitive Impairment in CKD in Children and Young Adults May Be Functional Rather than Structural

Children and adults with chronic kidney disease (CKD) often experience neurocognitive dysfunction. Children with CKD may have reduced performance in attention, memory, executive function, verbal and nonverbal reasoning, and spatial processing. Global cognitive performance may be reduced in adults with CKD; further, patients may experience specific cognitive impairments such as attention, memory and executive functioning, and dementia.

There is relatively little known about the neuroanatomic basis for the link between CKD and neurocognitive dysfunction. Most of the studies conducted previously among adults used subjective or nonquantitative imaging methods; most prior pediatric studies have used older imaging methods such as computed tomography.

Erum A. Hartung, MD, MTR, and colleagues recently conducted a cross-sectional study using advanced quantitative structural magnetic resonance imaging (sMRI) methods to form a more precise understanding of CKD-associated global and regional differences in brain structure in children and young adults with CKD. The study’s primary objective was to determine whether CKD affects brain structure and whether CKD-related neurocognitive dysfunction is associated with structural differences. Study results were reported in the American Journal of Kidney Diseases [2018;72(3):349-359].

The study compared grey matter, white matter, cerebrospinal fluid (CSF), and white matter lesion volumes in key regions of interest (ROIs) in the brain in children and young adults with CKD with those of healthy controls. The researchers sought to test the hypothesis that the patient population with CKD would have lower total brain grey matter volumes and higher CSF volumes compared with controls. It was also expected that the frontal, temporal, and parietal cortices would be particularly affected, and that these structural brain findings would be more prominent in patients with more severe CKD, defined as lower estimated glomerular filtration rate (eGFR) or history of a kidney transplant, and that there would be an association between neurocognitive performance and brain ROI volumes.

The analysis was performed as part of the cross-sectional NICK (Neurocognitive Assessment and Magnetic Resonance Imaging Analysis of Children and Adults with Chronic Kidney Disease) study. The NICK study included 92 participants with CKD and 70 participants in the control group. Of those, 88 with CKD and 66 in the control group completed brain MRI; 6 participants were excluded due to motion on the T1 scan; sMRI data were available on 85 in the CKD group and 63 in the control group; three current dialysis participants were excluded, leaving 82 in the CKD group and 63 in the control group aged 8 to 25 years in the final analysis.

At baseline, participants in the two groups were similar in age, sex, race, income level, insurance status, and maternal education. Mean duration of kidney disease for those in the CKD group was 9.9 years and mean eGFR was 48 mL/min/1.73 m2. Six participants on the CKD group had received their first renal replacement therapy at ≥5 years of age, 18.5% (n=15) had ever received dialysis, and 26% (n=21) had received a kidney transplant. Prematurity was more prevalent in the CKD group than in the control group (34% vs 16%; P=.01).

In unadjusted analyses, compared with the control group, participants in the CKD group had lower grey matter volumes in whole brain (P=.04), cortex (P=.04), and left parietal (P=.04) ROIs. None of the differences remained statistically significant following adjustment for multiple comparisons using the false discovery rate (FDR) correction method. Following adjustment for age and sex, there were nominally lower grey matter volumes in whole-brain, cortex, and left parietal ROIs in the CKD group compared with the control group, but this did not reach statistical significance.

In the CKD group, there was an association between lower eGFR and higher white matter volume in whole-brain and frontal ROIs. However, the differences were not significant following multiple comparisons correction.

Following adjustment for age and sex, in comparisons of participants with CKD with eGFRs <45 versus ≥45 mL/min/1.73 m2, the lower eGFR group had higher frontal white matter volumes than the higher eGFR group (P=.04). When transplant recipients were excluded from the analyses, there were no significant differences between the two eGFR groups.

In comparisons of kidney transplant recipients versus those without a kidney transplant, following adjustment for age and sex, kidney transplant recipients had lower grey matter volumes in whole-brain (P=.01), frontal (total: P=.02; left: P=.02; right: P=.01), and parietal (left: P=.01; right: P=.03) ROIs. Further, transplant recipients had higher whole-brain white matter volumes (P=.04). None of the differences remained statistically significant after FDR correction for multiple comparisons; however, Q values were borderline (Q=.06) for whole-brain grey matter, right-frontal grey matter, and left-parietal grey matter.

Finally, there was no association between neurocognitive performance and ROI volumes in patients in the CKD group.

Limitations cited by the authors included the inability to assess changes in brain structure and kidney function over time, and limiting the analysis to prespecified ROIs and neurocognitive domains.

“In summary,” the researchers said, “we found that early stage CKD in children and young adults is associated with relatively subtle differences in brain structure, but these differences are more prominent in kidney transplant recipients, including global and regional cerebral atrophy and increased global white matter volume. However, these differences in brain structure were not associated with neurocognitive performance, suggesting a functional rather than structural basis for neurocognitive impairment in CKD. Further studies using other imaging modalities may help elucidate the functional basis for CKD-related neurocognitive dysfunction.”

Takeaway Points

  1. In a recent cross-sectional study, researchers sought to determine whether CKD affects brain structure and whether CKD-related neurocognitive dysfunction is associated with structural differences.
  2. Study participants were 85 individuals with CKD stages 2 to 5 and 63 healthy controls, aged 8 to 25 years.
  3. There may be an association between CKD in children and adults and lower grey matter and higher white matter in some brain regions of interest; differences between the CKD group and controls were more pronounced in recipients of a kidney transplant.