Hemodialysis.com

Publication:

Author Interview: Dr. Stephen R. Hooper

Publication:
Neurocognitive functioning of children and adolescents with mild-to-moderate chronic kidney disease.

Hooper SR, Gerson AC, Butler RW, Gipson DS, Mendley SR, Lande MB, Shinnar S, Wentz A, Matheson M, Cox C, Furth SL, Warady, BA. (2011).Clin J Am Soc Nephrol 6: 1824-1830.

The relationship between chronic kidney disease (CKD) and neurodevelopmental dysfunction in children has been examined using various approaches for the past several decades, with key studies dating back into the early 1980s. Despite this history, most of the published studies have focused on children with ESRD and/or samples comprised of different degrees of severity, with few studies focusing on the neurocognitive functioning of children with mild-to-moderate CKD.
The Chronic Kidney Disease in Children (CKiD) prospective cohort study is a multicenter longitudinal investigation which focuses exclusively on children with mild-to-moderate CKD. Utilization of the CKiD sample has provided one of the first large-scale opportunities to examine the neurocognitive functioning of children and adolescents with mild to moderate CKD. Several key findings were uncovered from this study.

First, consistent with earlier investigations of children with severe CKD or mixed severity samples, our results revealed that most children with mild-to-moderate CKD had average intelligence, age-appropriate academic skills, and intact attention/executive functioning.

Despite this initial observation, when individual patients were examined it was discovered that a large percentage of them were at-risk (i.e., being at least one standard deviation below the mean of the tests) for neurocognitive dysfunction. This was particularly the case for the parent ratings of executive functioning, where percentages ranged from 27% to 40% of the group falling within the at-risk range. These types of executive deficits have been reported in children with severe and end-stage kidney disease, as well as in the adult population, but their appearance this early in the disease process is noteworthy, particularly given that the CKD will worsen over time.

Although lower iohexol-based GFR (iGFR) was not significantly related to neurocognitive dysfunction after controlling for a host of other variables, we did find that a higher iGFR was significantly related to a lower risk for executive dysfunction.

Finally, after statistically controlling for other variables in the analyses, the results also demonstrated that participants with elevated proteinuria had lower verbal intelligence, lower overall IQ, and poorer attention regulation. These participants tended to be adolescent and have glomerular disease, hypertension, and immunosuppressive medication use more so than the nonproteinuric group.

One of the striking unexpected findings related to the relative lack of association between the disease-related variables and neurocognition. In particular, it was noteworthy that the presence of glomerular diagnosis, iGFR, and the percentage of life with CKD did not relate to neurocognitive dysfunctions. We are pondering the possibility that there may be a specific threshold for disease burden before neurocognitive impairment will be evident in this population.

Additionally, hypertension was not clearly related to neurocognitive dysfunction. There were some hints that hypertension could be related to lower attention/executive function capabilities, but our findings likely were limited by a large percentage of our sample taking hypertensive medications.

Finally, about 18% of the sample had a history of low birth weight, and it was remarkable how this variable contributed to at-risk status for neurocognitive dysfunction as well as to lower IQ, academic achievement, and attention/executive capabilities. It is well known that low birth weight can exert a strong influence on later neurocognitive functioning, but its influence on neurocognitive functioning in pediatric CKD is an important observation. In that regard, children having both CKD and low birth weight may have “double jeopardy” with respect to later neurodevelopment and learning. Our findings also would suggest that a parallel set of observations could be made for the presence of co-morbid seizure disorders in children with mild-to-moderate CKD.

There are several “take away” findings from this large multisite study.

First, the results reflect that most children and adolescents with CKD actually show relatively intact neurocognitive functioning. This is a reassuring finding, but one that could fluctuate as the disease severity progresses, and the longitudinal component of the CKiD Study will permit tracking these children over time.

Given this, the second “take away” point indicates the need for regular neurodevelopmental surveillance of children with CKD, particularly from a neurocognitive perspective. Although children with CKD are followed regularly with respect to their kidney disease, it is not clear that their neurocognitive or academic skills are followed in as routine a fashion. Additionally, ongoing neurodevelopmental surveillance will allow for ongoing examination of the effect of specific disease-related variables that may become increasingly more apparent with disease progression and subsequent increased disease burden.

Third, a significant percentage of children and adolescents with CKD will show mild to moderate neurocognitive dysfunction, and it will be important for these cases to receive attention so as to minimize any secondary effects from the CKD and associated neurocognitive problems.

Fourth, in addition to monitoring key disease-related variables related to CKD (e.g., hypertension, iGFR, elevated proteinuria), it will be important to consider variables, such as the presence of a seizure disorder or a history of low birth weight, as critical to neurodevelopmental outcomes in children with CKD.

Finally, catching these types of problems as early as possible will assist neprhologists in seeking early interventions to improve their day-to-day functioning and quality of life. Speculatively, successful use of and response to these early interventions also may facilitate ongoing positive medical compliance and, hopefully, better health outcomes for children with CKD

These findings point to the need for greater interdisciplinary team involvement for children and adolescents with CKD. In particular, the utilization of a pediatric psychologist or pediatric neuropsychologist to the team would be critical to assist with the routine neurodevelopmental surveillance that probably should occur for all patients.

Various team members also should survey the available resources in their state and/or region to determine the most effective services to address the child’s needs in an efficient fashion.

In particular, given the neurocognitive difficulties that are present in a large percentage of the pediatric CKD population, linkages to school services and understanding their policies and practices would be critical. Knowledge and linkages to the resources of the state and/or region also will be critical as the disease burden worsens and the need for additional assistance increases.

Background and objectives Few data exist on the neurocognitive functioning of children with mild-to-moderate chronic kidney disease (CKD). The primary objectives of this paper are (1) to determine the neurocognitive status in this population and (2) to identify sociodemographic and health-status variables associated with neurocognitive functioning.

Design, setting, participants, & measurements This was a cross-sectional study of 368 children, aged 6 to 16 years, from the Chronic Kidney Disease in Children (CKiD) cohort. Median iGFR was 43 ml/min per 1.73 m2, and the median duration of CKD was 8.0 years. Approximately 26% had underlying glomerular disease.
Measures of intelligence, academic achievement, attention regulation, and executive functioning were obtained at study entry. The prevalence of neurocognitive deficits was determined by comparing participant scores on each
measure of neurocognitive functioning with normative data. The association between hypothesized predictors of neurocognitive dysfunction was evaluated using multivariate regression analyses.

Results Neurocognitive functioning was within the average range for the entire group; however, 21% to 40% of participants scored at least one SD below the mean on measures of intelligence quotient (IQ), academic achievement, attention regulation, or executive functioning. Higher iohexol-based GFR (iGFR) predicted a lesser risk for poor performance on measures of executive function. Participants having elevated proteinuria (i.e., urine protein/creatinine _2) scored lower on verbal IQ, full-scale IQ, and attention variability than those without elevated proteinuria.

Conclusions Whereas most children with mild-to-moderate CKD have no major neurocognitive deficits, a substantial percentage did show neurocognitive dysfunction that places them at risk for poor long-term educational and occupational outcomes.