The best magazine
Materials and Methods
CKiD is a prospective cohort study of children aged 1–16 years at recruitment with CKD (estimated GFR (eGFR) 30–90 ml/min per 1.73 m), which is conducted at 48 pediatric nephrology centers in North America. Details of the study design and methods have been published previously. In this analysis, we have looked at all subjects aged 6 and older, and results are limited to ages for which there are normative data. Children with intellectual disabilities and those with genetic syndromes with central nervous system manifestations were excluded by study design. The protocol was approved by the Institutional Review Boards of all centers.
Kidney Function
The CKiD study includes a reliable method of GFR measurement by iohexol clearance at defined study time points. However, we separated neurocognitive testing dates from clearance studies to avoid the distraction of iohexol infusion and phlebotomy. Previous analysis of the iohexol clearance data has allowed the generation of a validated, accurate method to estimate GFR using serum creatinine, cystatin C, and blood urea nitrogen measurements, and this was used to provide a contemporaneous eGFR at the time of neurocognitive assessment.
Assessment of Attention and EF
The study protocol includes a battery of age-appropriate tests of EF performed by child psychologists at defined intervals (6 months after study entry, 1.5 years later, and then every 2 years). This analysis contains data from the first visit at which each subject had the complete EF battery done, and thus some subjects were more than 16 years of age by the time of testing. EF measures included the CPT-II, which is a computer-based task that requires the subject to touch the mouse or space bar in response to visual stimuli (that is, letters on computer screen) that are presented at the rate of about one per second over approximately a 14-min testing period. The CPT-II provides information about the child's omission and commission error rates, reaction time, and response variability, which represent an assessment of sustained attention and inhibitory control. The CPT-II measures are scaled to a mean=50 and s.d.=10; higher scores indicate worse performance.
Included in the battery was the D–KEFS in which subjects are asked to move a set of disks from one peg to another; only one disk can be moved at a time, and a larger disk cannot be placed over a smaller disk. The task becomes more complicated as the number of disks increases and it draws upon skills of planning, reasoning, problem-solving, and inhibitory control. Age-based norms for the Total Achievement Score (representing time required to complete the task correctly) are available for subjects aged 8 years and older, and only that age group is included in analysis. The D–KEFS scores are scaled to a mean=10 and s.d.=3; lower scores indicate worse performance.
Also included was an assessment of working memory using the WISC or WAIS (for those subjects over age 16 at testing) Digit Span Backward tasks, in which subjects are asked to repeat a list of verbally presented numbers in reverse order. Age-based standardized norms for Digit Span Backward have a mean=10 and s.d.=3, and lower scores indicate worse performance. In addition to the EF measures, we determine the estimated level of IQ for each subject using Full-4 from the Wechsler Abbreviated Scale of Intelligence.
Statistical Analysis
Performance on tests of EF was compared across the range of GFR and CKD duration. Duration of CKD was determined by parent report of the child's medical history and onset of disease at the first study visit and then corroborated with the nephrologist's records.
To address the primary research question, we identified subjects with poor performance on a test of EF, which was defined as a score ≥1.5 s.d. below the normal population mean on any of the five EF measures. On D–KEFS and Digit Span Backward, poor performance corresponds to a scaled score ≤5.5; on CPT measures, poor performance corresponds to a T score of ≥65. We stratified our sample by performance on each EF measure and examined the distributions of the primary exposures, duration of CKD, and eGFR, by testing for differences with Wilcoxon rank-sum tests. We used logistic regression to predict the likelihood of executive dysfunction by level of GFR or duration of CKD, adjusting for a targeted group of covariates or potential confounders including age, race, maternal education, household income, IQ, blood pressure, premature birth, and proteinuria. These covariates were selected from a wide range of potentially relevant patient characteristics based upon previously published neurocognitive findings from the CKiD study. To clarify the impact of renal disease on neurocognitive function, eGFR and duration of CKD were examined in separate models. We also explored adjusted linear regression models to assess potential effects on the continuous EF scales across the full range of performance.
We considered whether a global assessment might be a useful tool to identify relevant exposures affecting EF in this population. To test this, we created a composite score of the five EF measures by rescaling the scores to have the same mean and directionality and accounting for within- and between-measure variance, allowing an overall score of 'poor' and 'not poor'.
Source: ...