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Article Neurocognitive and Educational Outcomes in Children and Adolescents with CKD A Systematic Review and Meta-Analysis Kerry Chen , Madeleine Didsbury, Anita van Zwieten , Martin Howell , Siah Kim, Allison Tong, Kirsten Howard, Natasha Nassar, Belinda Barton, Suncica Lah, Jennifer Lorenzo, Giovanni Strippoli, Suetonia Palmer, Armando Teixeira- Pinto, Fiona Mackie, Steven McTaggart, Amanda Walker, Tonya Kara,a Jonathan C. Craig, and Germaine Wong Due to the number of contributing authors, Abstract the affiliations are Background and objectives Poor cognition can affect educational attainment, but the extent of neurocognitive provided in the impairment in children with CKD is not well understood. This systematic review assessed global and domain- Supplemental Material. specific cognition and academic skills in children with CKD and whether these outcomes varied with CKD stage. Correspondence: Design, setting, participants, & measurements Electronic databases were searched for observational studies of Dr. Kerry Chen, Centre children with CKD ages 21 years old or younger that assessed neurocognitive or educational outcomes. Risk of bias for Kidney Research, fi – The Kids Research was assessed using a modi ed Newcastle Ottawa scale. We used random effects models and expressed the Institute, The estimates as mean differences with 95% confidence intervals stratified by CKD stage. Children’s Hospital at Westmead, Sydney Results Thirty-four studies (25 cross-sectional, n=2095; nine cohort, n=991) were included. The overall risk of bias School of Public Health, The University was high because of selection and measurement biases. The global cognition (full-scale intelligence quotient) of of Sydney, children with CKD was classified as low average. Compared with the general population, the mean differences Hawkesbury Road and (95% confidence intervals) in full-scale intelligence quotient were 210.5 (95% confidence interval, 213.2 to 27.72; Hainsworth Street, all CKD stages, n=758), 29.39 (95% confidence interval, 212.6 to 26.18; mild to moderate stage CKD, n=582), Sydney, New South 216.2 (95% confidence interval, 233.2 to 0.86; dialysis, n=23), and 211.2 (95% confidence interval, 217.8 to 24.50; Wales, Australia 2145. Email: kerry.chen@ transplant, n=153). Direct comparisons showed that children with mild to moderate stage CKD and kidney sydney.edu.au transplants scored 11.2 (95% confidence interval, 2.98 to 19.4) and 10.1 (95% confidence interval, 21.81 to 22.0) full- scale intelligence quotient points higher than children on dialysis. Children with CKD also had lower scores than the general population in executive function and memory (verbal and visual) domains. Compared with children without CKD, the mean differences in academic skills (n=518) ranged from 215.7 to 21.22 for mathematics, from 29.04 to 20.17 for reading, and from 214.2 to 2.53 for spelling. Conclusions Children with CKD may have low-average cognition compared with the general population, with mild deficits observed across academic skills, executive function, and visual and verbal memory. Limited evidence suggests that children on dialysis may be at greatest risk compared with children with mild to moderate stage CKD and transplant recipients. Clin J Am Soc Nephrol 13: 387–397, 2018. doi: https://doi.org/10.2215/CJN.09650917 Introduction neurocognitive function varies substantially across CKD has known detrimental effects on children’s studies. A number of studies have identified lower physical health and wellbeing, and there is increasing nonverbal intelligence quotient (IQ) and motor per- awareness of its potential effect on neurocognitive formance in children with kidney disease compared function, academic outcomes, and mental health (1– with healthy age-matched controls (6–11). Some have 3). The pathophysiologic effects of advanced uremia found no significant differences in memory (verbal and anemia seen in CKD may alter brain metabolism and nonverbal) between children with and without and impair neurocognitive function through changes to CKD (11). Others have reported specificdeficits in neuronal myelination and synaptic development (4). complex auditory attention, verbal working memory, CKD treatment regimens can also disrupt school atten- and the recognition of emotional states (11,12). The dance and compromise academic achievement, with extent and patterns of neurocognitive and academic potential consequences for educational and vocational impairment in children may also vary by CKD stage. attainment as children transition to adulthood (4,5). The overall IQ score for children treated with hemo- In children and adolescents with CKD, evidence dialysis seems to be lower than that of children with regarding the effect of reduced kidney function on moderate stage CKD and those with kidney www.cjasn.org Vol 13 March, 2018 Copyright © 2018 by the American Society of Nephrology 387 388 Clinical Journal of the American Society of Nephrology transplants (13–15). Nonetheless, several studies have found Test [CPT]), executive function (Behavior Rating Inventory of improvement in IQ, attention, and mental processing speed Executive Function [BRIEF]), and memory (Wide Range after transplantation (16,17). Assessment of Memory and Learning [WRAML]). Where The objectives of this systematic review were to assess possible, comparisons were also made between children with global and domain-specificneurocognitivefunctionand CKD and age-matched controls. Unless specified, a lower academic skills in children with CKD and whether these score was indicative of poorer outcomes. We also compared outcomes worsen with advancing CKD stage. the overall and domain-specific cognitive and academic estimates between CKD stages if data were available. Heterogeneity was assessed using the Cochran Q test Materials and Methods and the I2 statistic. Possible sources of heterogeneity were We conducted a systematic review of observational studies investigated using subgroup analysis and metaregression on the basis of standard methods and reporting criteria in the (random effects model) on publication year, country of Meta-Analysis of Observational Studies in Epidemiology publication, study design, study size, and risk of bias. guidelines (18). The protocol was registered with the Interna- Meta-regression was conducted where ten or more studies tional Prospective Register of Systematic Reviews for the specified outcomes were available. Funnel plots (CRD42014013056). were generated to assess publication bias. All analyses Studies were included if they assessed neurocognitive or were conducted using Review Manager Version 5 and , academic outcomes in children and adolescents (ages 21 Comprehensive Meta-Analysis Version 3. years old) with CKD. We included studies where compar- isons were made between patients with CKD and patients without CKD, either indirectly using normative population Results data or directly using matched non-CKD cohorts and/or Characteristics of Included Studies between different stages of CKD (mild to moderate stage Of 7437 records identified, 34 studies (25 cross-sectional CKD, dialysis, and transplant). Prospective cohort and and nine cohort) with 3086 children and adolescents were cross-sectional designs were eligible. included, and findings from 18 studies were used in the MEDLINE, Embase, and PsycINFO were searched from meta-analyses (Figure 1). The studies were conducted in nine database inception to December 2016, with no language countries, including the United States (59%), The Netherlands restrictions (Supplemental Table 1). We also hand searched the (9%), Canada (6%), Egypt (6%), and Finland (6%). Of those reference lists of identified studies and review articles. Two with CKD (n=2446), 2092 (85.5%) had mild to moderate stage authors (K.C. and A.v.Z.) screened the titles and abstracts, and CKD, 115 (4.7%) were on dialysis, and 239 (9.8%) had kidney they independently assessed the full-text articles to identify transplants. Neurocognitive function was measured by 51 studies that satisfied the inclusion criteria. A third reviewer different tests, with full-scale IQ being the most frequently (G.W.) adjudicated where disagreement arose. reported outcome followed by verbal and performance IQ, Data extraction was carried out using standard extraction memory, attention, and executive function (Figure 2 A–C, forms. Studies reported in non-English languages were trans- Supplemental Tables 2 and 3, Table 1). lated before assessment. Where more than one publication of a study existed, only the publication with the most complete Risk of Bias and Publication Bias Assessment data was included for meta-analysis. We sought data on the The overall risk of bias was high (Figure 3). Seventeen age, socioeconomic status, duration of CKD of study partic- (50%) studies described the recruitment strategies, and only ipants, and raw scores from cognitive testing from study nine (26%) had participation rates of .70%. Twenty-three fi authors and reported these ndings where available. (68%) studies did not report an objective assessment of the exposure (CKD) with blinding to outcome. Conduct of Risk of Bias Assessment statistical methods was adequate in 21 (62%) studies. Ad- Two authors (K.C. and M.D.) undertook independent justment for confounders was conducted in 20 (59%) studies. quality assessment of the included studies. We used a mod- Asymmetry of funnel plots also indicated potential publica- ified Newcastle–Ottawa scale to assess risk of bias. Differences tion bias for studies conducted with different CKD groups