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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 comparisons 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 were resolved by discussion until consensus was achieved. (Supplemental Table 4).

Data Synthesis and Statistical Analyses Association between CKD and Neurocognitive Functioning We summarized the overall and domain-specific neuro- Intelligence (25 Studies, 1446 Patients). The Wechsler cognitive and academic estimates between those with and scales were the most frequently used instruments (n=22 without CKD using random effects models stratified by CKD studies) for assessing intellectual functioning (20). The stage (mild to moderate stage CKD, dialysis, and transplant), mean global intelligence (full-scale IQ) of all children with with the summary estimates expressed as mean differences CKD was 92.7 (SD=16.2; n=758). Children with mild to with 95% confidence intervals (95% CIs) and effect sizes moderate stage CKD scored 29.39 (95% CI, 212.6 to reported as Cohen d values. We compared estimates against 26.18), 28.07 (95% CI, 212.2 to 23.90), and 28.73 (95% CI, the population norm for standardized measures of intelli- 212.8 to 24.69) points on full-scale IQ, verbal IQ, and gence (Wechsler scales: mean =100, SD=15; IQ classification: performance IQ, respectively, compared with the general 80–89 low average, 90–109 average, and 110–119 high population. The full-scale IQ, verbal IQ, and performance average [19]), academic achievement (Wechsler Individual IQ scores were 216.2 (95% CI, 233.2 to 0.86), 214.1 (95% Achievement Test [WIAT] and Wide Range Achievement CI, 233.2 to 4.89), and 215.5 (95% CI, 237.3 to 6.21) points Test [WRAT]), attention (Conners Continuous Performance for children on dialysis compared with the general Clin J Am Soc Nephrol 13: 387–397, March, 2018 Neurocognition in Children and Adolescents with CKD, Chen et al. 389

Figure 1. | Preferred reporting items for systematic reviews and meta-analyses flowchart. Thirty-four studies were included for systematic review (25 cross-sectional, 9 cohort). IQ, intelligence quotient. population, respectively. Transplant recipients scored stage. Compared with children on dialysis, the average 211.2 (95% CI, 217.8 to 24.50), 24.06 (95% CI, 211.1 to full-scale IQ score was 11.2 points higher among children 3.03), and 210.5 (95% CI, 216.8 to 24.13) points on full- with mild to moderate stage CKD (95% CI, 2.98 to 19.4). scale IQ, verbal IQ, and performance IQ, respectively, There may be improvement after transplantation, because compared with the population norm. transplant recipients scored 10.1 (95% CI, 21.81 to 22.0) For studies that included age-matched controls, children points higher in full-scale IQ than children on dialysis. with mild to moderate stage CKD scored 216.2 (95% CI, Attention (13 Studies, 1366 Patients). The Conners' CPT 222.2 to 210.1), 27.84 (95% CI, 213.5 to 22.20), and 211.7 (five studies; n=875) was the most frequently used instrument (95% CI, 213.2 to 210.2) points on full-scale IQ, verbal IQ, to assess attention, with higher T scores (mean =50; SD=10) and performance IQ, respectively, compared children reflecting greater impairment (21,22). Children with CKD without kidney disease. Children on dialysis scored had equivalent scores to the population norms for variabil- 229.5 (95% CI, 238.5 to 220.5), 218.2 (95% CI, 223.2 to ity (0.10; 95% CI, 21.02 to 1.22), but scores were 1.70 (95% 213.2), and 221.1 (95% CI, 229.2 to 213.0) points on full- CI, 0.32 to 3.08) and 1.70 (95% CI, 0.58 to 2.82) points higher scale IQ, verbal IQ, and performance IQ, respectively, in the omission and commission errors subtests, respec- compared with age-matched controls. The full-scale IQ for tively, and 21.80 (95% CI, 23.39 to 20.21) points in reaction transplant recipients was 229.4 (95% CI, 253.9 to 24.77) time. points compared with age-matched controls. Five studies Executive Function (11 Studies, 1390 Patients) Five (n=168) compared intellectual functioning across CKD studies used the BRIEF, which assesses executive function 390 Clinical Journal of the American Society of Nephrology

Figure 2. | Significant deficits observed in children with CKD. A shows full-scale intelligence quotient (IQ) between children with and without CKD. B shows verbal and performance IQ between children with and without CKD. 95% CI, 95% confidence interval; df, degree of freedom; IV, inverse variance; SE, SEM. using T scores (mean =50; SD=10), where higher T scores memory, and number/letter) and visual memory (picture indicate greater impairment (23). Compared with the general memory, design memory, and finger windows). Transplant population, children with mild to moderate stage CKD recipients scored 211.2 (95% CI, 218.4 to 24.01), 211.3 (95% scored 3.50 (95% CI, 1.97 to 5.03), 5.90 (95% CI, 4.34 to CI, 217.1 to 25.55), and 213.4 (95% CI, 219.5 to 27.26) 7.46), and 5.20 (95% CI, 3.64 to 6.76) points higher in the points in verbal, visual and screening memory, respectively, behavior regulation, metacognition, and global executive compared with the general population. indices of the BRIEF, respectively. This pattern of deficit was less consistent among transplant recipients, who scored Association between CKD and Educational Outcomes (Ten 21.70 (95% CI, 25.88 to 2.48) points compared with the Studies, 808 Patients) general population in behavior regulation but 11.4 (95% CI, TheWIATandtheWRATwereusedtomeasureacademic 0.75 to 22.1) and 5.80 (95% CI, 22.11 to 13.7) points higher in skills (mean =100; SD=15), with outcomes commonly reported the metacognition and global executive indices, respectively. as reading, mathematics, and spelling (Supplemental Table 2) Memory (12 Studies, 615 Patients) The WRAML was (24–26). Overall, the scores for children with mild to moderate used to assess three domains of memory (verbal memory, stage CKD were 25.19 (95% CI, 28.14 to 22.25), 21.50 (95% visual memory, and acquisition of new learning) in five CI, 22.56 to 20.43), 29.58 (95% CI, 216.0 to 3.12), and 25.18 studies (mean =10; SD=3). Compared with children without (95% CI, 28.28 to 22.09) points in reading accuracy, reading CKD, those with mild to moderate stage CKD scored lower comprehension, mathematics, and spelling, respectively, com- in the subtests of verbal memory (story memory, sentence pared with the general population (Supplemental Figure 1). Clin J Am Soc Nephrol 13: 387–397, March, 2018 Neurocognition in Children and Adolescents with CKD, Chen et al. 391

Figure 2. | Continued.

Transplant recipients scored 29.31 (95% CI, 216.7 to 21.90), Effect of Disease Severity, Duration of Disease, and Age 212.0 (95% CI, 213.0 to 211.1), and 29.20 (95% CI, 211.2 to of Onset 27.25) points on reading accuracy, mathematics, and spelling Four studies considered the effect of variables, such disease compared with the general population. The greatest differ- severity, duration of CKD, and age of disease onset, on enceswereseeninchildrenondialysis,whoscored210.0 (95% intellectual functioning and academic achievement in chil- CI, 211.5 to 28.46), 211.0 (95% CI, 212.5 to 29.46), and 215.0 dren across different CKD stages. Compared with children (95% CI, 216.5 to 213.5) points on reading, arithmetic, and with mild to moderate stage CKD, those with advanced stage spelling, respectively, compared with the population norm. CKD had lower full-scale IQ and memory function. Chil- In studies with healthy age-matched controls, children dren with prolonged duration of reduced kidney function with mild to moderate stage CKD scored 20.60 (95% CI, seemed to have lower memory function and academic 28.44 to 7.24) and 27.25 (95% CI, 28.89 to 25.62) points in skills compared with children who experienced shorter reading accuracy and mathematics, respectively, but 0.40 duration of CKD. However, the age of disease onset did not (95% CI, 21.42 to 2.22) and 4.76 (95% CI, 20.52 to 10.0) seem to have an effect on the neurocognitive function in points higher in reading comprehension and spelling, re- children with CKD. spectively. For children on dialysis, reading, arithmetic, and spelling scores were lower by 210.0 (95% CI, 211.9 to 28.08), Subgroup Analyses 23.00 (95% CI, 24.92 to 21.08), and 211.0 (95% CI, 212.5 to With the exception of study sample size, the full-scale IQ 29.46) points, respectively, compared with the age-matched scores did not signiﬁcantly vary with our hypothesized study- controls. Transplant recipients scored 27.00 (95% CI, 28.39 level sources of variability (Figure 4). The mean differences in to 25.61), 210.0 (95% CI, 211.4 to 28.61), and 27.00 (95% CI, full-scale IQ scores between children with CKD and the 28.39 to 25.61) points on reading, arithmetic, and spelling, general population in studies published before and after 2010 respectively, compared with age-matched controls. Com- were 210.4 (95% CI, 212.5 to 28.31) and 29.57 (95% CI, 217.2 pared with patients on dialysis, transplant recipients gener- to 21.98), respectively. The estimates for cross-sectional and ally had higher scores on reading, arithmetic, and spelling. cohort studies were 29.37 (95% CI, 213.4 to 25.34) and 29.56 392 Clinical Journal of the American Society of Nephrology

Figure 2. | Continued.

(95% CI, 214.1 to 25.02), respectively. For studies with a without CKD. Deficits were most apparent in global smaller sample size (n#50), the mean difference was 211.7 intelligence, with children achieving average to low- (95% CI, 212.9 to 210.4) compared with 26.77 (95% CI, 212.4 average full-scale IQ scores compared with the population to 21.10) for studies with larger sample sizes (n.50). norm. Compared with children with mild to moderate stage CKD and those with kidney transplants, children on dialysis had the lowest full-scale IQ scores. The specific Metaregression fi A metaregression (n=11 studies) of full-scale IQ scores patterns of de cit were evident for attention, memory, and executive function domains. For attention, children with between children with and without CKD showed that fi study sample size was the only variable that explained the CKD had dif culty in holding information and shifting high degree of heterogeneity between studies (b=5.31; from one stimulus to another but displayed intact function SEM=2.01; P,0.01). The coefficients in full-scale IQ scores in other areas. Children with CKD had reduced visual and between children with CKD and the general population verbal memory compared with children without CKD. For were 20.51 (SEM=3.01; P=0.86), 0.05 (SEM=3.67; P=0.99), executive function, children with CKD had reduced meta- 2.58 (SEM=2.51; P=0.30), and 20.72 (SEM=3.41; P=0.83) for cognitive skills but preserved behavioral regulation com- year of publication (before and after 2010), study designs pared with children without CKD. Similar to scores of (cross-sectional versus cohort studies), country (the United intellectual functioning, academic achievement also ranged States versus not the United States), and study quality (low from average to low average among children with CKD versus high risk of bias), respectively. compared with the general population, with the greatest deficit observed in mathematics. Clinically, scores at least one SD lower in overall in- Discussion telligence and domain-specific cognitive domains place chil- Our study findings suggest that children with CKD may dren at increased risk of poor academic performance at have lower intellectual functioning compared with children school, reduced quality of life, and poor mental health, with Clin J Am Soc Nephrol 13: 387–397, March, 2018 Neurocognition in Children and Adolescents with CKD, Chen et al. 393

Table 1. Characteristics of included studies Table 1. (Continued)

Characteristic N (%) Characteristic N (%) c Study related Subtests Year of publication Full-scale IQ 21 (62) 2010 to present 14 (41) Verbal IQ 18 (53) 2000–2009 10 (29) Performance IQ 16 (47) Pre-2000 10 (29) Reading 8(24) Country of publication Arithmetic 8(24) United States 20 (59) Spelling 4(12) The Netherlands 3(9) Canada 2(6) IQ, intelligence quotient. Egypt 2(6) aTwo studies did not specify. Finland 2(6) bThere is overlap in the number of studies. Other 5(15) cNot all studies reporting outcomes contained data suitable for No. of patients per study (n) meta-analysis. 0–99 27 (79) 100–199 5(15) 200+ 2(6) Study design potential implications for vocational attainment and financial Cross-sectional 25 (74) independence as they transition into adulthood (3,27,28). We Cohort 9(26) found at least one-SD lower intellectual functioning (full- Patient related Mean age, yra scale IQ and performance IQ), academic achievement (total 0–6 3(9) achievement subdomain), and executive function (initiation, 7–12 16 (47) sustaining, and BRIEF metacognition index subtests) among 13+ 13 (38) b children with CKD compared with those without CKD. Stages of CKD Because the SEM of measurement is approximately five Mild to moderate stage CKD 25 (74) fi Dialysis 6(18) standard points for Wechsler scales and our ndings show Transplant 15 (44) differences of more than five standard points, such cognitive Use of controlsb deficits would be considered clinically meaningful (29). Direct non-CKD controls 19 (56) There are also data suggesting that children with more Normative population data 28 (82) Test related advanced stage CKD, increased duration of disease, and Outcome domains younger age of disease onset are associated with an Intelligence 25 (74) increased risk of neurocognitive deficit and poor academic Academic achievement 10 (29) outcomes (15,28). By comparison, studies of children with Attention 11 (32) epilepsy also show deficits in intellectual functioning: full- Executive function 9(26) Memory 12 (35) scale IQ mean =85.0 (SD=20.7; n=69), verbal IQ mean =86.9 Intelligence (SD=22.6; n=69), and performance IQ mean =84.5 (SD=19.4; Wechsler scales (IQ) 22 (65) n=69) (30). Prior studies have reported that children with Stanford Binet Intelligence Test 2(6) chronic illnesses, such as chronic liver disease (CLD), Test of nonverbal intelligence 1(3) experienced comparable deficit in intellectual functioning, Other 9(26) fi Attention attention, and executive function, but a signi cant im- Conners Continuous Performance Task 5(15) provement in IQ scores was observed in children with CLD c Continuous performance task 3(9) after transplantation (full-scale IQ mean =94.7; SD=13.5; Gordon Diagnostic System 2(6) effect size =20.35; n=134) (31,32). Such deficit in cognitive Other 8(24) Executive function function may be associated with poorer academic achieve- Behavior Rating Inventory of Executive Function 5(15) ment, health literacy, and psychologic wellbeing in chil- Delis–Kaplan Executive Function System 2(6) dren with CLD (33–35). – Halstead Reitan Category Test 2(6) Unique metabolic, biochemical, and neurodegenerative Other 8(24) Memory mechanisms may partially explain why the overall in- Wide range assessment of memory and learning 5(15) tellectual function of children with CKD is reduced com- Nonverbal selective reminding test 2(6) pared with the general population. Increased plasma levels Other 9(26) of uremic solutes may cause neurotoxic demyelination and Academic achievement impair synaptic development (4). CKD-related anemia and Wechsler Individual Achievement Test 6(18) Wide Range Achievement Test 3(9) poor nutrition may also reduce the delivery of oxygen to Peabody Individual Achievement Test 2(6) the brain and alter brain metabolism, whereas secondary Other 2(6) hyperparathyroidism can potentially interfere with neuro- transmission by increasing calcium levels in the brain (36). It has been proposed that dialysis itself may also lead to cognitive impairment through rapid changes in BP causing brain hypoperfusion as well as the presence of gaseous microemboli, edema, and ongoing deposition of hemosid- erin in cerebral parenchyma (37). These intradialytic BP changes in addition to the increased severity and chronicity 394 Clinical Journal of the American Society of Nephrology

Risk of Bias of Included Studies (Newcastle-Ottawa Scale)

Participant selection

Study participation and attrition

Confounder identification

Assessment of outcomes Low risk High risk Assessment of confounders Unclear

Ascertainment of exposure

Adequacy of measure(s)

0% 20% 40% 60% 80% 100% Percentage of Included Studies

Figure 3. | Risk of bias assessment. The overall risk of bias was high. of pathophysiologic effects related to ESKD, such as involvement of relevant expert teams may inform the hypertension and poor nutrition, may result in reduced development of a comprehensive post-transplant rehabil- cognitive function among children on dialysis compared itation service for children and adolescents with CKD. with those with other CKD stages. This systematic review synthesizes all published evi- Alongside inherent pathophysiologic factors, the thera- dence on global and domain-specific cognitive and aca- peutic regimens for CKD may also compromise academic demic outcomes in children and adolescents with CKD, achievement (2,3). First, the frequency of sleep disturbances including variation across CKD stage. Our findings pro- in children with CKD may result in poor concentration, vide relevant prognostic information on how advancing excessive daytime sleepiness, and lower academic perfor- CKD stage may affect neurocognitive and academic out- mance (38). Second, the interactions of complex medication comes, while exploring the effect of publication year, study routines and strict dialysis cycles may decrease attentional size, and study design on these outcomes. Nonetheless, control, working memory, and executive function, cogni- there are some potential limitations. We combined all tive domains that are important to children’sabilityto studies of intelligence (IQ) that used the Wechsler scales. acquire, understand, and retain information in social and However, the composition of IQ has evolved over time, educational environments (37,39,40). In particular, lower with newer versions of Wechsler Intelligence Scale for mathematic scores may be attributed to the reduced overall Children focusing more on fluid reasoning than crystal- neurocognitive function of children with CKD, with fluid lized knowledge (46–48). Because of the variability in reasoning and processing speed having direct and indirect exposure groups, outcome measures, and reporting, meta- effects on mathematic ability (41,42). Studies examining the analyses of estimates for outcomes including attention, relationship between intelligence (full-scale IQ) and aca- executive function, and memory were not possible. Al- demic performance reported a moderate and statistically though heterogeneity was partially explained by study significant correlation moderated by factors, such as size, not all of the sources of variability could be identified. attendance, motivation, home and school environments, Small sample sizes may have insufficient power and thus, and cultural demographics (3,43). Across all CKD stages, reduce the likelihood that a statistically significant result we have shown that intelligence is largely consistent with reflects a true effect. Nonetheless, additional factors to academic skills. Third, ongoing dialysis sessions and re- consider for the unexplained heterogeneity include partic- covery from transplant surgeries may reduce the amount ipant demographics, such as age, socioeconomic status, and regularity of time spent in the classroom, with chronic severity of CKD, duration of disease, and age of onset; absenteeism potentially preceding loss of interest, with- study-level factors, such as use of direct controls (versus drawal, and poor school progression (2,44,45). Importantly, normative population data); and the breadth of outcome low-average cognition and academic skills suggest that measures used. Data on CKD-related clinical factors, such children receiving dialysis may be at greatest risk com- as low birth weight, hypertension, and nutritional status, pared with those in other CKD groups. Therefore, educa- were also not available from included studies. As such, we tional support programs should aim to minimize deficits in could not assess the potential confounding effects of these attention, memory, and executive function and navigate factors on the association between reduced kidney function the logistic restrictions of rigorous management regimens and cognition in our analyses. Lastly, because the majority for CKD through a multidisciplinary approach. Identifica- of studies have cross-sectional designs, we could not assess tion of the biopsychosocial factors associated with im- the longitudinal change in cognitive function with advanc- proved neurocognitive and educational outcomes and the ing CKD stage. Clin J Am Soc Nephrol 13: 387–397, March, 2018 Neurocognition in Children and Adolescents with CKD, Chen et al. 395

Figure 4. | Subgroup analyses of full-scale intelligence quotient in children with and without CKD (mild to moderate stage CKD). 95% CI, 95% conﬁdence interval; df, degree of freedom; IV, inverse variance; SE, SEM.

Our findings suggest that children with CKD may have on dialysis, the magnitude and domain-specificpatterns low-average neurocognitive and academic outcomes. of effect are not clearly defined in the existing literature. Although cognition seems to worsen with advancing Well conducted longitudinal studies assessing multiple CKD, with the poorest performance observed in children cognitive domains as children progress through different 396 Clinical Journal of the American Society of Nephrology

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Lawry KW, Brouhard BH, Cunningham RJ: Cognitive functioning plantation 79: 1252–1256, 2005 and school performance in children with renal failure. Pediatr 35. Kennard BD, Stewart SM, Phelan-McAuliffe D, Waller DA, Nephrol 8: 326–329, 1994 Bannister M, Fioravani V, Andrews WS: Academic outcome in 14. Hooper SR, Gerson AC, Butler RW, Gipson DS, Mendley SR, long-term survivors of pediatric liver transplantation. J Dev Behav Lande MB, Shinnar S, Wentz A, Matheson M, Cox C, Furth SL, Pediatr 20: 17–23, 1999 Warady BA: Neurocognitive functioning of children and ado- 36. Arnold R, Issar T, Krishnan AV, Pussell BA: Neurological com- lescents with mild-to-moderate chronic kidney disease. Clin J Am plications in chronic kidney disease. JRSM Cardiovasc Dis 5: Soc Nephrol 6: 1824–1830, 2011 2048004016677687, 2016 15. Brouhard BH,Donaldson LA, Lawry KW,McGowanKR,DrotarD, 37. Madero M, Sarnak MJ: Does hemodialysis hurt the brain? 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38. Etgen T: Kidney disease as a determinant of cognitive decline and academic achievement, and socioeconomic status among dementia. Alzheimers Res Ther 7: 29, 2015 fourth-grade children. J Sch Health 81: 417–423, 2011 39. Duquette PJ: Attention functions in children with pediatric 46. Kanaya T, Ceci SJ, Scullin MH: The rise and fall of IQ in special ed: chronic kidney disease. PhD Dissertation. Chapel Hill, NC, Historical trends and their implications. J Sch Psychol 2003; 41: 453–465 University of North Carolina at Chapel Hill, 2007 47. Flynn JR: Problems with IQ gains: The huge vocabulary gap. J 40. Puerta L: Relationship between cognitive processes and Psychoeduc Assess 28: 412–433, 2010 academic performance in high school students. Psychol Av 48. Wicherts JM, Dolan CV,Hessen DJ, Oosterveld P, van Baal GCM, Discip 9: 85–100, 2015 Boomsma DI, Spange MM: Are intelligence tests measurement 41. Taub GE, Floyd RG, Keith TZ, McGrew KS: Effects of general and invariant over time? Investigating the nature of the Flynn effect. broad cognitive abilities on mathematics achievement. Sch Intelligence 32: 509–537, 2004 Psychol Q 23: 187–198, 2008 42. Reeve RA, Waldecker C: Evidence-based assessment and in- Received: September 1, 2017 Accepted: December 11, 2017 tervention for dyscalculia and maths disabilities in school psychology. In: Handbook of Australian School Psychology, aDeceased. edited by Thielking M, Terjesen MD, Cham, Switzerland, Springer, 2017, pp 197–213 Published online ahead of print. Publication date available at www. 43. Kaufman SB, Reynolds MR, Liu X, Kaufman AS, McGrew KS: Are cognitive g and academic achievement g one and the same? An cjasn.org. exploration on the Woodcock-Johnson and Kaufman tests. In- “ telligence 40: 123–138, 2012 See related Patient Voice, Responsive Designed Interventions 44. Quarles D: An Analysis of Tardiness, Absenteeism, and Academic Are Needed to Support Positive Outcomes of Children and Achievement of 9th Grade Students in a Selected School District Adolescents with CKD,” on pages 357–358. in Southeastern Georgia, Orangeburg, South Carolina, ProQuest Dissertations Publishing, 2011 This article contains supplemental material online at http://cjasn. 45. Baxter SD, Royer JA, Hardin JW, Guinn CH, Devlin CM: asnjournals.org/lookup/suppl/doi:10.2215/CJN.09650917/-/ The relationship of school absenteeism with body mass index, DCSupplemental. Supplemental material is neither peer-reviewed nor thoroughly edited by CJASN. The authors alone are responsible for the accuracy and presentation of the material.

Supplementary Table 1 – Search strategy

Table 1: Summary of search strategies including MESH terms, text words and combinations used in MEDLINE, Embase, and PsycINFO searches (via OvidSP)

Keyword MEDLINE Embase PsycINFO

Population = Children Exp Child/ OR Child$.tw OR Exp Child/ OR Child$.tw OR Exp Pediatrics/ OR Exp Childhood and/or adolescents Girl$.tw OR Boy$.tw or Girl$.tw OR Boy$.tw OR Development/ OR Exp Adolescent P?ediatric$.tw OR Exp Pediatrics/ OR P?ediatric$.tw OR Exp pediatrics/ OR Development/ OR Child$.tw OR Girl$.tw OR Adolescent/ OR Adolescen$.tw OR Exp Adolescent/ OR Adolescen$.tw Boy$.tw OR P?ediatric$.tw OR Teen$.tw OR Youth$.tw OR Young OR Teen$.tw OR Youth$.tw OR Exp Adolescen$.tw OR Teen$.tw OR Youth$.tw Adult/ OR Young adult.tw young adult/ OR Young adult.tw OR Young adult.tw

Exposure = CKD1 Exp Kidney Diseases/ OR (kidney Exp kidney disease/ OR (kidney adj3 Exp Kidney Diseases/ OR exp Kidneys/ OR (mild-to-moderate adj3 (insuffic$ or diseas$)).tw OR (insuffic$ or diseas$)).tw OR (renal exp Organ OR Transplantation/ or exp stage CKD, dialysis, (renal adj3 (insuffic$ or diseas$)).tw adj3 (insuffic$ or diseas$)).tw OR Dialysis/ OR (kidney adj3 (insuffic$ or and kidney (pre-dialysis or predialysis).tw OR (pre-dialysis or predialysis).tw OR diseas$)).tw OR (renal adj3 (insuffic$ or transplantation) exp Renal Replacement Therapy/ OR exp renal replacement therapy/ OR diseas$)).tw OR (pre-dialysis or H?emodialysis.tw OR (hemofiltration (hemodialysis or haemodialysis).tw predialysis).tw OR (hemodialysis or or haemofiltration).tw OR OR (hemofiltration or haemodialysis).tw OR (hemofiltration or (hemodiafiltration or haemofiltration).tw OR haemofiltration).tw OR (hemodiafiltration or haemodiafiltration).tw OR dialysis.tw (hemodiafiltration or haemodiafiltration).tw OR dialysis.tw OR OR (PD or CAPD or CCPD or haemodiafiltration).tw OR dialysis.tw (PD or CAPD or CCPD or APD).tw OR APD).tw OR peritoneal dialysis.tw OR (PD or CAPD or CCPD or peritoneal dialysis.tw OR (end-stage renal or (end-stage renal or end-stage kidney APD).tw OR peritoneal dialysis.tw end-stage kidney or endstage renal or or endstage renal or endstage OR (end-stage renal or end-stage endstage kidney).tw OR (ESRF or ESKF or kidney).tw OR (ESRF or ESKF or kidney or endstage renal or endstage ESRD or ESKD).tw OR (chronic kidney or ESRD or ESKD).tw OR (chronic kidney).tw OR (ESRF or ESKF or chronic renal).tw OR (CKF or CKD or CRF kidney or chronic renal).tw OR (CKF ESRD or ESKD).tw OR (chronic or CRD).tw OR ur?emi$.tw OR (dysfunction or CKD or CRF or CRD).tw OR kidney or chronic renal).tw OR (CKF adj3 (kidney or renal)).tw OR nephrotic ur?emi$.tw OR Kidney or CKD or CRF or CRD).tw OR syndrome.tw Transplantation/ OR (dysfunction ur?emi$.tw OR exp kidney

Supplemental material is neither peer-reviewed nor thoroughly edited by CJASN. The authors alone are responsible for the accuracy and presentation of the material.

Keyword MEDLINE Embase PsycINFO

adj3 (kidney or renal)).tw OR exp transplantation/ OR (dysfunction adj3 Nephrotic Syndrome/ OR nephrotic (kidney or renal)).tw OR exp syndrome.tw OR exp Nephrosis, nephrotic syndrome/ OR nephrotic Lipoid/ OR lipoid nephrosis.tw syndrome.tw OR exp lipoid nephrosis/ OR lipoid nephrosis.tw

Methodology = Exp Epidemiologic Studies/ OR Case Exp epidemiology/ OR Case Exp Epidemiology/ OR Case control.tw OR Observational studies, control.tw OR (cohort adj (study or control.tw OR (cohort adj (study or (cohort adj (study or studies)).tw OR Cohort inclusive of case- studies)).tw OR Cohort analy$.tw OR studies)).tw OR Cohort analy$.tw OR analy$.tw OR (follow up adj (study or control, cross- (follow up adj (study or studies)).tw (follow up adj (study or studies)).tw studies)).tw OR (observational adj (study or sectional and cohort OR (observational adj (study or OR (observational adj (study or studies)).tw OR Longitudinal.tw OR studies studies)).tw OR Longitudinal.tw OR studies)).tw OR Longitudinal.tw OR Retrospective.tw OR Cross sectional.tw OR Retrospective.tw OR Cross Retrospective.tw OR Cross Exp Meta Analysis/ OR Exp “Literature sectional.tw OR exp Meta-Analysis/ sectional.tw OR Exp meta-analysis/ Review”/ OR Meta anal$.tw OR OR Meta anal$.tw OR Metaanaly$.tw OR Meta anal$.tw OR Metaanaly$.tw Metaanaly$.tw OR (systematic adj (review$1 OR (systematic adj (review$1 or OR (systematic adj (review$1 or or overview$1)).tw overview$1)).tw overview$1)).tw

Comparator = None No search strategy No search strategy No search strategy

Outcome = All Exp Emotional Intelligence/ OR exp Exp intelligence/ OR exp emotional Exp Emotional Intelligence/ OR exp neurocognitive Intelligence Tests/ OR exp intelligence/ OR exp intelligence test/ Intelligence Quotient/ OR exp Cognitive domains Intelligence/ OR Intell$.tw OR OR Intell$.tw OR Academic.tw OR Ability/ OR exp Intelligence Measures/ OR Academic.tw OR Educatio$.tw OR Educatio$.tw OR exp education/ OR exp Intelligence/ OR exp Academic Aptitude/ exp Education/ OR IQ.tw OR exp IQ.tw OR exp cognition assessment/ OR exp Academic Achievement/ OR exp Cognition OR Cogniti$.tw OR OR exp cognition/ OR Cogniti$.tw Academic Failure/ OR exp Psychological (outcome adj3 (education$ or OR (outcome adj3 (education$ or Assessment/ OR exp Cognition/ OR exp academic or cogniti$ or psychological academic or cogniti$ or Psychological Development/ OR exp or neurocognit$)).tw OR (intell$ adj3 neurocognit$)).tw OR (intell$ adj3 Cognitive Impairment/ OR exp Cognitive (quotient or def$ or abilit$)).tw OR (quotient or def$ or abilit$)).tw OR Processes/ OR exp Performance Tests/ OR exp Neuropsychological Tests/ OR exp neuropsychological test/ OR exp Attention/ OR exp Executive Function/ (Wechsler adj3 (intelligen$ or (Wechsler adj3 (intelligen$ or OR exp Memory/ OR exp Verbal Fluency/

Supplemental material is neither peer-reviewed nor thoroughly edited by CJASN. The authors alone are responsible for the accuracy and presentation of the material.

Keyword MEDLINE Embase PsycINFO

memory)).tw OR (neuropsychiatric memory)).tw OR (neuropsychiatric OR exp Learning Disorders/ OR exp Visual adj3 (inventory or battery)).tw OR adj3 (inventory or battery)).tw OR Perception/ OR exp Spatial Perception/ OR exp Executive function/ OR exp Neuropsychological test$.tw OR exp exp Perceptual Motor Processes/ OR exp Memory/ OR exp Language/ OR exp executive function/ OR exp memory/ Response Inhibition/ OR exp “Interference Attention/ OR exp Language/ OR exp OR exp language/ OR exp attention/ (Learning)”/ OR exp Dual Task Performance/ language tests/ OR exp Visual OR exp language test/ OR exp depth OR exp discrimination learning/ OR exp perception/ OR exp Space perception/ perception/ OR Psychomotor “interference (learning)”/ OR exp nonverbal OR Psychomotor performance.tw OR performance.tw OR Global cognitive learning/ OR exp perceptual learning/ OR exp Global cognitive function$.tw OR function$.tw OR (memory adj3 spatial learning/ OR exp verbal learning/ OR (memory adj3 (disorder$ or function$ (disorder$ or function$ or def$)).tw Intell$.tw OR Academic.tw OR Educatio$.tw or def$)).tw OR (Speed adj1 OR (Speed adj1 (processing or OR IQ.tw OR Cogniti$.tw OR (outcome adj3 (processing or response)).tw OR response)).tw OR (visuospatial adj1 (education$ or academic or cogniti$ or (visuospatial adj1 (perception or (perception or function)).tw OR neurocognit$)).tw OR (intell$ adj3 (quotient function)).tw OR Verbal fluency.tw Verbal fluency.tw OR (flexibility adj1 or def$ or abilit$)).tw OR exp OR (flexibility adj1 (cognitive or (cognitive or mental)).tw OR exp neuropsychological test/ OR (Wechsler adj3 mental)).tw OR exp “Inhibition “inhibition (psychology)”/ OR exp (intelligen$ or memory)).tw OR (Psychology)”/ OR exp Problem problem solving/ OR Social (neuropsychiatric adj3 (inventory or Solving/ OR Social cognition.tw OR cognition.tw OR (Set adj1 (switching battery)).tw OR Neuropsychological test$.tw (Set adj1 (switching or shifting)).tw or shifting)).tw OR exp mathematics/ OR Psychomotor performance.tw OR Global OR exp Mathematics/ OR exp OR exp discrimination learning/ OR cognitive function$.tw OR (memory adj3 discrimination learning/ OR exp exp spatial learning/ OR exp (disorder$ or function$ or def$)).tw OR verbal learning/ OR (neurocognit$ verbalization/ OR (neurocognit$ adj3 (Speed adj1 (processing or response)).tw OR adj3 (function$ or defic$ or (function$ or defic$ or abnormal$ or (visuospatial adj1 (perception or function)).tw abnormal$ or outcome$ or disorder$ outcome$ or disorder$ or illness$ or OR Verbal fluency.tw OR (flexibility adj1 or illness$ or problem$ or wellbeing problem$ or wellbeing or well-being (cognitive or mental)).tw OR Social or well-being or health or stress)).tw or health or stress)).tw cognition.tw OR (Set adj1 (switching or shifting)).tw OR exp Cognitive Processing Speed/ OR exp Reaction Time/ OR (function$ adj3 neurocognit$).tw

1CKD: chronic kidney disease 3

Supplemental material is neither peer-reviewed nor thoroughly edited by CJASN. The authors alone are responsible for the accuracy and presentation of the material.

Supplementary Table 2: Characteristics of included studies

Title, author Country Study Age (years) n Patient cohort Study outcome(s) Outcome measure(s) Follow‐up type Mean (SD) Test(s) Indices/subtest(s) time 1 Amr 2013 Egypt Cross‐ 10.4 (3.80) 12 CKD I‐V Intelligence WISC (Arabic version) Full‐Scale IQ N/A sectional 13.5 (2.90) 12 Dialysis Verbal IQ 11.9 (3.70) 12 Control group Performance IQ 2 Bawden 2004 Canada Cross‐ 11.8 (3.27) 22 CKD I‐V Intelligence WISC‐III Full‐Scale IQ N/A sectional Verbal IQ Academic achievement WIAT, WRAT3, Woodcock Reading Performance IQ Mastery Test‐R Reading 11.7 (3.09) 22 Control group Writing Language Expressive One‐Word Picture Arithmetic Vocabulary Test Word Attack Reading Comprehension Memory WRAML, Nonverbal Selective Reminding Test

Visuomotor skills Developmental Test of Visual‐Motor Integration, Grooved Pegboard Test, Finger‐Tapping Test 3 Brouhard 2000 United States Cross‐ 13.7 (0.44) 26 Dialysis Intelligence Test of Nonverbal Intelligence‐2 Reading N/A sectional 36 Transplant recipients Spelling 13.7 (0.38) 62 Control group Academic achievement WRAT Arithmetic 4 Crittenden 1985 United States Cohort R: 0.50‐16 66 CKD I‐V Intelligence WISC, WISC‐R, WAIS, Stanford‐Binet Full‐Scale IQ Median:

Intelligence Test, Cattell Infant 14 months Intelligence Test, Bayley Scales of (R: 2‐40 Infant Development months) 5 Crocker 2002 Canada Cross‐ 12.0 (2.41) 24 CKD I‐V Intelligence WISC‐III Full‐Scale IQ N/A sectional Verbal IQ Academic achievement WIAT, WRAT3, Woodcock Reading Performance IQ Mastery‐R Reading Spelling Language Expressive One‐Word Picture Arithmetic Vocabulary Test Word Attack Reading Comprehension Memory WRAML, Nonverbal Selective Verbal Learning Reminding Test Sentence Memory Finger Windows Visuomotor skills Developmental Test of Visual‐Motor Integration, Grooved Pegboard Test, Finger‐Tapping Test 4

Supplemental material is neither peer-reviewed nor thoroughly edited by CJASN. The authors alone are responsible for the accuracy and presentation of the material.

6 Duquette 2008 United States Cross‐ 12.7 (3.32) 30 CKD I‐V Attention Tower of London Test Total Move N/A sectional Gordon Diagnostic System Total Execution Time Keith Auditory Continuous Total Correct Performance Test Mean Response Time Ruff Figural Fluency Test Correct Variability 11.7 (3.36) 41 Control group WRAML/WASI scores as co‐variates Total Correct Correct Variability Perseverations Total Finger Windows Number/Letter 7 Duquette 2007 United States Cross‐ 12.7 (3.32) 30 CKD I‐V Intelligence WASI Full‐Scale IQ N/A sectional Verbal IQ Academic achievement WIAT‐II Performance IQ 11.7 (3.36) 41 Control group Word Reading Mathematics Reasoning Spelling 8 El‐Shazly 2010 Egypt Cross‐ ‐ 25 CKD I‐V Intelligence Stanford‐Binet Intelligence Test Full‐Scale IQ N/A sectional ‐ 25 Control group 9 Falger 2008 Switzerland Cross‐ Median: 14.1 27 Transplant recipients Intelligence WISC‐III or Kaufman Assessment Full‐Scale IQ N/A sectional (R: 6.50‐17.0) Battery for Children Verbal IQ Performance IQ 10 Fennell 1990 United States Cohort 13.6 (no SD) 56 CKD I‐V Intelligence WISC‐R, WAIS‐R Verbal IQ 6, 12, and Digit Span 18months Attention Continuous Performance Task Color Progressive Standard Progressive ‐ 56 Control group Memory Buschke Restricted Reminding Memory, Auditory Consonant Trigrams, Distraction Paradigm

Visuomotor skills Raven’s Matrices, Beery‐Butenica Development Test 11 Fennell 1984 United States Cohort 11.7 (3.70) 20 CKD I‐V‐to‐transplant Intelligence WISC Full‐Scale IQ 1 month; recipients Verbal IQ 1 year Academic achievement Peabody Individual Achievement Test Performance IQ 12.6 (3.90) 18 Control group Digit Span

Attention Continuous Performance Task

Executive function Halstead‐Reitan Category Test

Memory Free recall memory task

Supplemental material is neither peer-reviewed nor thoroughly edited by CJASN. The authors alone are responsible for the accuracy and presentation of the material.

12 Gipson 2006 United States Cross‐ 13.4 (3.20) 20 CKD I‐V Intelligence WASI Numbers Reversed N/A sectional Vigilance subtest Executive function Tower of London Test, Gordon Diagnostic System, Controlled Oral 12.9 (2.90) 18 Control group Word Association Test, Ruff Figural Fluency Test, Woodcock‐Johnson‐III

Memory WRAML 13 Gulleroglu 2013 Turkey Cross‐ 12.6 (3.20) 20 CKD I‐V Attention Cancellation Test N/A sectional 13.5 (3.40) 20 Transplant recipients Language Visual and Auditory Number Assay Test 14.2 (2.10) 20 Control group

Visuomotor skills Bender‐Gestalt Test 14 Haavisto 2012 Finland Cross‐ 11.1 (3.20) 50 Transplant recipients Intelligence WISC‐III Full‐Scale IQ N/A sectional Verbal IQ Attention NEPSY‐II Performance IQ Language Auditory Attention and Memory Response Set Visuomotor skills Speeded Naming Comprehension of Instru. Visuomotor Precision Memory for Designs Memory for Faces World List Interference Design Copying Geometric Puzzles Affect Recognition 15 Hartmann 2015 Germany Cross‐ 8.30 (1.40) 15 Transplant recipients Intelligence HAWIK‐III, CFIT Full‐Scale IQ N/A sectional Verbal IQ Performance IQ CFT 1 sum 1 CFT 1 sum 2 CFT 1 sum 3 CFT 20‐R 16 Hartung 2016 United States Cross‐ 16.3 (3.90) 92 CKD I‐V Executive function Penn CNB Conditional Exclusion N/A sectional Episodic memory Continuous Performance Complex cognition Short Letter N‐Back Social cognition Word Memory Face Memory

Supplemental material is neither peer-reviewed nor thoroughly edited by CJASN. The authors alone are responsible for the accuracy and presentation of the material.

16.0 (4.00) 69 Control group Visual Object Learning Verbal Reasoning Matrix Reasoning Line Orientation Emotion Identification Emotion Differentiation Age Differentiation 17 Hartung 2014 United States Cross‐ Median: 66 CKD I‐V Intelligence WASI or WPPSI‐R or Mullen Scales of Full‐Scale IQ N/A sectional 7.60 Early Learning Verbal IQ Performance IQ Academic achievement WIAT‐II‐A Numerical operations Word reading Attention Conners’ CPT‐II Spelling Conners’ Kiddie CPT Total achievement

Executive function BRIEF

18 Hooper 2015 United States Cross‐ 16.2 (3.87) 90 CKD I‐V Executive function BRIEF (Parent‐Report and Adult Behavior regulation index N/A sectional versions) Metacognition index 16.0 (3.96) 69 Control group Global executive composite

19 Hooper 2011 United States Cross‐ Median 13.0 368 CKD I‐V Intelligence WASI Full‐Scale IQ N/A sectional (IQR, 15.0; Verbal IQ R: 6.00‐17.0) Academic achievement WIAT‐II‐A Performance IQ Basic reading Attention Conners’ CPT‐II Spelling Numerical operations Executive function BRIEF (Parent‐Report) Total achievement 20 Hulstijn‐ The Cohort 2.43 (1.58) 15 CKD I‐V Cognitive development Bayley Developmental Scales <2.6y OR 6 months Dirkmaat 1995 Netherlands 2.58 (1.48) 16 Dialysis McCarthy Developmental Scales >2.6y 21 Hulstijn‐ The Cross‐ 3.08 18 CKD I‐V Cognitive development Bayley Developmental Scales <2.6y OR N/A Dirkmaat 1992 Netherlands sectional (R: 1.75‐2.92) McCarthy Developmental Scales >2.6y 2.92 18 Control group (R: 2.25‐3.75) 22 Icard 2010 United States Cohort 7.80 (no SD) 28 CKD I‐V Intelligence Mullen Scales of Early Learning <5y OR Full‐Scale IQ 1 year WASI 6‐18y 10.7 (no SD) 6 Transplants recipients 10.3 (no SD) 23 Control group 23 Johnson 2013 United States Cross‐ 11.0 (no SD) 12 Transplant recipients Intelligence WISC‐IV Full‐Scale IQ N/A

Supplemental material is neither peer-reviewed nor thoroughly edited by CJASN. The authors alone are responsible for the accuracy and presentation of the material.

sectional 10.0 (no SD) 9 Control group Verbal comprehension Academic achievement WIAT‐II‐A Perceptual reasoning Working memory Executive function BRIEF (Parent‐Report) Processing speed Word reading Memory WRAML2 Numerical operations Spelling Total achievement 24 Kuyer 1990 The Cohort 9.50 (R: 4‐14) 20 CKD I‐V‐to‐transplant Intelligence WISC‐R or WPPSI‐R Full‐Scale IQ Mean 1.7y Netherlands recipients Verbal IQ (R: 5‐47 Performance IQ months) 25 Lawry 1994 United States Cross‐ 14.9 (3.33) 11 Dialysis Intelligence WISC‐R or WAIS‐R Full‐Scale IQ N/A sectional Verbal IQ 13.9 (3.22) 13 Transplant recipients Academic achievement Woodcock‐Johnson Test Performance IQ Mathematics Reading Written language 26 Madden 2003 United Cross‐ 5.84 (2.96) 16 Dialysis/transplant Intelligence WISC‐III, Griffiths Mental Development Full‐Scale IQ N/A Kingdom sectional recipients Scales 27 Mendley 2015 United States Cross‐ Median: 13.0 340 CKD I‐V Intelligence WISC Tower Task N/A sectional (IQR: 7) Digit Span Backward Attention Conners’ CPT‐II

Executive function D‐KEFS 28 Mendley 1999 United States Cohort 14.2 (3.50) 9 CKD I‐V‐to‐transplant Intelligence WISC‐III or WAIS‐R Full‐Scale IQ 1 year recipients Verbal IQ Attention Conners’ CPT, Stroop Color‐Word Performance IQ Naming Test, Cognitive Abilities Test

Executive function Paced Auditory Serial Addition Test OR the Children’s Paced Auditory Serial Addition Test

Language Buschke Selective Reminding Test

Visuomotor skills Meier Visual Discrimination Test, Trail‐ making Test, Grooved Pegboard Test 29 Molnar‐Varga Hungary Cross‐ 13.4 (2.40) 35 Transplant recipients Intelligence Woodcock‐Johnson International Edition Full‐Scale IQ N/A 2016 sectional Verbal Ability 13.4 (2.50) 35 Control group Thinking Ability Cognitive Efficiency 30 Qvist 2002 Finland Cross‐ 8.00 (R: 7‐12) 33 Transplant recipients Intelligence WISC‐R Full‐Scale IQ N/A 8

Supplemental material is neither peer-reviewed nor thoroughly edited by CJASN. The authors alone are responsible for the accuracy and presentation of the material.

sectional Verbal IQ Attention NEPSY Performance IQ Language Memory Visuomotor skills 31 Rasbury 1986 United States Cohort 12.8 (3.61) 18 CKD I‐V –to‐dialysis Intelligence CFIT 4 days 13.1 (3.56) 18 Control group Memory Paired associate learning test 32 Rasbury 1983 United States Cohort 11.2 (3.40) 14 CKD I‐V‐to‐transplant Intelligence WISC Full‐Scale IQ 1 month recipients Verbal IQ Academic achievement Peabody Individual Achievement Test Performance IQ 11.0 (3.60) 14 Control group Mathematics Attention Continuous Performance Task Reading Information Executive function Halstead‐Reitan Category Test

Memory Free Recall Memory Task 33 Ruebner 2016 United States Cross‐ 16.3 (3.94) 92 CKD I‐V Attention WISC‐IV‐I, Conners CPT‐II Vocabulary N/A sectional Similarities Executive function BRIEF (Parent Report, Adult versions), Matrix Reasoning D‐KEFS Block Design 15.9 (3.93) 70 Control group Total Achievement Language WASI Move Accuracy Ratio Digit Span Forward Memory WISC‐IV‐I, WMS‐III Digit Span Backward Spatial Span Forward Visuomotor skills WASI, WMS‐III Spatial Span Backward 34 Slickers 2007 United States Cross‐ 12.5 (3.20) 29 CKD I‐V Intelligence WASI Vocabulary N/A sectional Block design Attention Gordon Diagnostic System Similarities Matrix reasoning Memory WRAML

Supplemental material is neither peer-reviewed nor thoroughly edited by CJASN. The authors alone are responsible for the accuracy and presentation of the material.

Legend BRIEF: Behavior Rating Inventory of Executive Function CFIT: Culture Fair Intelligence Test CKD: chronic kidney disease Conners CPT-II: Conners Continuous Performance Test, Second Edition Conners Kiddie CPT: Conners Kiddie Continuous Performance Test D-KEFS: Delis-Kaplan Executive Function System HAWIK-III: Hamburg-Wechsler-Intelligenztests für Kinder (Hamburg-Wechsler-Intelligence Scale for Children), Third Edition NEPSY: Developmental Neuropsychological Assessment NEPSY-II: Developmental Neuropsychological Assessment, Second Assessment Penn CNB: Penn’s Computerized Neurocognitive Battery WAIS-R: Wechsler Adult Intelligence Scale - Revised WASI: Wechsler Abbreviated Scale of Intelligence WIAT: Wechsler Individual Achievement Test WIAT-II-A: Wechsler Individual Achievement Test-II Abbreviated WISC: Wechsler Intelligence Scale for Children WISC-R: Wechsler Intelligence Scale for Children - Revised WISC-III: Wechsler Intelligence Scale for Children, Third Edition WISC-IV: Wechsler Intelligence Scale for Children, Fourth Edition WMS-III: Wechsler Memory Scale, Third Edition WPPSI-III: Wechsler Preschool and Primary Scale of Intelligence, Third Edition WRAML: Wide Range Assessment of Memory and Learning WRAML2: Wide Range Assessment of Memory and Learning, Second Edition WRAT: Wide Range Achievement Test WRAT3: Wide Range Achievement Test-Revised, Third Edition

Supplemental material is neither peer-reviewed nor thoroughly edited by CJASN. The authors alone are responsible for the accuracy and presentation of the material.

Supplementary Table 3 – Clinical outcomes

TABLE 2.1 Clinical outcomes – comparison with healthy controls Outcome Domains n (studies) N (CKD) Mean (SD) N (controls) Mean (SD) Mean difference [95% CI] Effect size (Cohen’s d) P I2 (%) MILD‐TO‐MODERATE STAGE CKD Intelligence* Full‐Scale IQ ‐ Healthy controls 6 132 89.3 (15.3) 134 106 (13.6) ‐16.2 [‐22.2, ‐10.1] 1.15 <0.001 81 ‐ Normative data 11 582 94.2 (16.1) ‐ 100 (15) ‐9.39 [‐12.6, ‐6.18] 0.63 <0.001 87 Verbal IQ ‐ Healthy controls 4 84 91.6 (16.2) 93 102 (13.4) ‐7.84 [‐13.5, ‐2.20] 0.70 0.006 61 ‐ Normative data 8 505 96.2 (16.7) ‐ 100 (15) ‐8.07 [‐12.2, ‐3.90] 0.54 <0.001 90 Performance IQ ‐ Healthy controls 4 84 88.7 (14.3) 93 101 (12.4) ‐11.7 [‐13.2, ‐10.2] 0.92 <0.001 0 ‐ Normative data 8 505 94.3 (15.9) ‐ 100 (15) ‐8.73 [‐12.8, ‐4.69] 0.58 <0.001 91 CFIT 1 18 13.6 (2.78) 18 14.8 (2.64) ‐1.20 [‐2.97, 0.57] 0.44 0.18 ‐ Academic achievement Single Word Reading ‐ Healthy controls 2 52 96.9 (15.0) 63 100 (14.8) ‐0.60 [‐8.44, 7.24] 0.21 0.88 71 ‐ Normative data 4 444 96.0 (16.8) ‐ 100 (15) ‐6.38 [‐11.6, ‐1.17] 0.43 0.02 94 Reading Comprehension ‐ Healthy controls 1 22 98.5 (2.60) 22 98.1 (3.50) 0.40 [‐1.42, 2.22] 0.13 0.67 ‐ ‐ Normative data 2 46 98.6 (11.4) ‐ 100 (15) ‐1.50 [‐2.57, ‐0.43] 0.10 0.006 0 Mathematics ‐ Healthy controls 2 52 92.8 (19.1) 63 105 (18.5) ‐7.25 [‐8.89, ‐5.62] 0.65 <0.001 24 ‐ Normative data 4 444 93.2 (14.5) ‐ 100 (15) ‐9.58 [‐16.0, ‐3.12] 0.64 0.004 95 Spelling ‐ Healthy controls 2 52 98.7 (16.1) 63 97.1 (15.6) 4.76 [‐0.52, 10.0] 0.10 0.08 44 ‐ Normative data 4 444 96.1 (17.5) ‐ 100 (15) ‐5.18 [‐8.27, ‐2.09] 0.35 0.001 80 WIAT scores ‐ Total Achievement Healthy controls 0 0 ‐ 0 ‐ ‐ ‐ ‐ ‐ Normative data 1 368 95.2 (17.8) ‐ 100 (15) ‐4.80 [‐6.62, ‐2.98] 0.32 <0.001 ‐ WRMT‐R ‐ Word Attack Healthy controls 1 22 93.0 (4.10) 22 90.5 (3.20) 2.50 [0.33, 4.67] 0.68 0.02 ‐ Normative data 2 46 91.9 (10.9) ‐ 100 (15) ‐7.16 [‐8.81, ‐5.52] 0.48 <0.001 0 Peabody scores ‐ Reading 2 34 37.2 (14.6) 32 38.4 (11.8) ‐1.08 [‐7.40, 5.23] 0.09 0.84 0 ‐ Mathematics 2 34 37.2 (14.2) 32 39.6 (16.3) ‐2.34 [‐9.68, 4.99] 0.16 0.63 0 ‐ General Information 2 34 32.4 (19.6) 32 32.5 (16.0) ‐0.12 [‐8.69, 8.45] 0.01 0.98 0 Attention Conners’ CPT (T‐scores) ‐ Omissions 1 368 51.7 (13.5) ‐ 50 (10) 1.70 [0.32, 3.08] 0.17 0.02 ‐ ‐ Commissions 1 368 51.7 (11.0) ‐ 50 (10) 1.70 [0.58, 2.82] 0.17 0.003 ‐ 11

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‐ Variability 1 368 50.1 (11.0) ‐ 50 (10) 0.10 [‐1.02, 1.22] 0.01 0.86 ‐ ‐ Reaction Time 1 368 48.2 (11.9) ‐ 50 (10) ‐1.80 [‐3.02, ‐0.58] 0.18 0.004 ‐ CPT (#/20) 1 20 14.8 (4.50) 18 14.7 (4.60) 0.10 [‐2.80, 3.00] 0.02 0.95 ‐ GDS Vigilance 1 29 96.0 (23.0) ‐ 100 (15) ‐4.00 [‐12.4, 4.37] 0.27 ‐0.35 ‐ Attention domainsa Focus/Execute ‐ Healthy controls 1 30 94.7 (11.4) 41 99.7 (8.51) ‐5.06 [‐9.91, ‐0.21] 0.50 0.04 ‐ ‐ Normative data 1 30 94.7 (11.4) ‐ 100 (15) ‐5.30 [‐9.38, ‐1.22] 0.35 0.01 ‐ Sustain ‐ Healthy controls 1 30 94.4 (16.2) 41 103 (14.8) ‐8.93 [‐16.3, ‐1.56] 0.55 0.02 ‐ ‐ Normative data 1 30 94.4 (16.2) ‐ 100 (15) ‐5.60 [‐11.4, 0.20] 0.37 0.06 ‐ Stability ‐ Healthy controls 1 30 87.2 (18.3) 41 97.0 (16.3) ‐9.75 [‐18.0, ‐1.52] 0.57 0.02 ‐ ‐ Normative data 1 30 87.2 (18.3) ‐ 100 (15) ‐12.8 [‐19.4, ‐6.25] 0.85 <0.001 ‐ Shift ‐ Healthy controls 1 30 91.5 (11.0) 41 95.7 (11.9) ‐4.24 [‐9.60, 1.12] 0.37 0.12 ‐ ‐ Normative data 1 30 91.5 (11.0) ‐ 100 (15) ‐8.50 [‐12.4, ‐4.56] 0.57 <0.001 ‐ Encode ‐ Healthy controls 1 30 88.7 (9.38) 41 99.5 (10.1) ‐10.8 [‐15.4, ‐6.23] 1.11 <0.001 ‐ ‐ Normative data 1 30 88.7 (9.38) ‐ 100 (15) ‐11.3 [‐14.7, ‐7.94] 0.75 <0.001 ‐ Cognitive development Bayley/McCarthy 1 15 90.3 (14.3) ‐ 100 (16) ‐9.70 [‐16.9, ‐2.46] 0.61 0.009 ‐ Developmental Scalesb Executive function BRIEF (T‐scores) ‐ Behavior Regulation Healthy controls 1 65 54.3 (11.9) 50 51.4 (12.8) 2.88 [‐1.69, 7.45] 0.23 0.22 ‐ Normative data 1 368 53.5 (11.1) ‐ 50 (10) 3.50 [1.97, 5.03] 0.35 <0.001 ‐ ‐ Metacognition Healthy controls 1 65 60.3 (12.0) 50 51.5 (11.2) 8.80 [4.54, 13.1] 0.76 <0.001 ‐ Normative data 1 368 55.9 (11.5) ‐ 50 (10) 5.90 [4.34, 7.46] 0.59 <0.001 ‐ ‐ Global Executive Healthy controls 1 65 58.7 (11.5) 50 51.5 (12.0) 7.21 [2.87, 11.6] 0.61 0.001 ‐ Normative data 1 368 55.2 (11.6) ‐ 50 (10) 5.20 [3.64, 6.76] 0.52 <0.001 ‐ HRPS Category Test 1 20 47.7 (21.1) 18 41.6 (23.0) 6.10 [‐7.99, 20.2] 0.28 0.40 ‐ Initiation ‐ Healthy controls 1 20 77.6 (19.2) 18 106 (14.5) ‐28.4 [‐39.2, ‐17.7] 1.67 <0.001 ‐ ‐ Normative data 1 20 77.6 (19.2) ‐ 100 (15) ‐22.4 [‐30.8, ‐14.0] 1.49 <0.001 ‐ Sustaining ‐ Healthy controls 1 20 85.0 (16.5) 18 101 (19.3) ‐15.6 [‐27.0, ‐4.10] 0.89 0.008 ‐ ‐ Normative data 1 20 85.0 (16.5) ‐ 100 (15) ‐15.1 [‐22.3, ‐7.83] 1.01 <0.001 ‐ Set‐Shifting ‐ Healthy controls 1 20 96.6 (17.3) 18 96.2 (13.5) 0.68 [‐11.0, 12.4] 0.03 0.91 ‐ ‐ Normative data 1 20 96.6 (17.3) ‐ 100 (15) ‐3.44 [‐11.0, 4.15] 0.23 0.37 ‐ Inhibition

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‐ Healthy controls 1 20 95.9 (19.2) 18 97.6 (19.5) ‐1.76 [‐14.1, 10.6] 0.04 0.78 ‐ ‐ Normative data 1 20 95.9 (19.2) ‐ 100 (15) ‐4.12 [‐12.5, 4.29] 0.27 0.34 ‐

Language EOWPVTc 1 24 97.9 (18.2) ‐ 100 (15) ‐2.10 [‐9.39, 5.18] 0.14 0.57 ‐ Memory WRAML scores ‐ General Memory Index 1 29 88.0 (16.0) ‐ 100 (15) ‐12.0 [‐17.8, ‐6.18] 0.80 <0.001 ‐ ‐ Finger Windows Healthy controls 2 42 8.77 (2.09) 40 9.14 (1.72) ‐0.37 [‐3.29, 2.55] 0.10 0.80 91 Normative data 2 42 8.77 (2.09) ‐ 10 (3) ‐1.01 [‐1.76, ‐0.26] 0.34 0.008 44 ‐ Sentence Memory Healthy controls 2 42 7.91 (2.08) 40 10.1 (1.61) ‐2.21 [‐5.02, 0.59] 0.51 0.12 91 Normative data 2 42 7.91 (2.08) ‐ 10 (3) ‐1.92 [‐2.21, ‐1.63] 0.64 <0.001 0 ‐ Verbal Learning Healthy controls 2 42 9.87 (2.03) 40 11.1 (1.59) ‐1.02 [‐1.35, ‐0.69] 0.32 <0.001 0 Normative data 2 42 9.87 (2.03) ‐ 10 (3) 0.06 [‐0.71, 0.84] 0.02 ‐0.87 47 ‐ Picture Memory Healthy controls 1 20 7.75 (2.99) 18 10.2 (2.81) ‐2.43 [‐4.27, ‐0.59] 0.39 0.010 ‐ Normative data 1 20 7.75 (2.99) ‐ 10 (3) ‐2.25 [‐3.56, ‐0.94] 0.75 <0.001 ‐ ‐ Design Memory Healthy controls 1 20 8.45 (1.91) 18 11.4 (3.02) ‐2.90 [‐4.53, ‐1.27] 0.50 <0.001 ‐ Normative data 1 20 8.45 (1.91) ‐ 10 (3) ‐1.55 [‐2.39, ‐0.71] 0.52 <0.001 ‐ ‐ Story Memory Healthy controls 1 20 7.95 (2.91) 18 11.5 (2.53) ‐3.52 [‐5.25, ‐1.79] 0.55 <0.001 ‐ Normative data 1 20 7.95 (2.91) ‐ 10 (3) ‐2.05 [‐3.33, ‐0.77] 0.68 0.002 ‐ ‐ Sound Symbol Healthy controls 1 20 9.70 (3.05) 18 12.9 (2.05) ‐3.24 [‐4.88, ‐1.60] 0.52 <0.001 ‐ Normative data 1 20 9.70 (3.05) ‐ 10 (3) ‐0.30 [‐1.64, 1.04] 0.10 0.66 ‐ ‐ Visual Learning Healthy controls 1 20 10.1 (2.25) 18 11.8 (2.97) ‐1.66 [‐3.35, 0.03] 0.31 0.05 ‐ Normative data 1 20 10.1 (2.25) ‐ 10 (3) 0.10 [‐0.89, 1.09] 0.03 0.84 ‐ ‐ Number/Letter Healthy controls 1 20 7.15 (1.95) 18 10.0 (2.18) ‐2.85 [‐4.17, ‐1.53] 0.57 <0.001 ‐ Normative data 1 20 7.15 (1.95) ‐ 10 (3) ‐2.85 [‐3.70, ‐2.00] 0.95 <0.001 ‐ NSRT (Z‐scores) ‐ Recall Healthy controls 1 22 ‐0.80 (0.20) 22 ‐0.20 (0.20) ‐0.60 [‐0.72, ‐0.48] 0.83 <0.001 ‐ Normative data 1 22 ‐0.80 (0.20) ‐ 0 (1) ‐0.80 [‐0.88, ‐0.72] 0.80 <0.001 ‐ ‐ Long Term Storage Healthy controls 1 22 ‐0.60 (0.20) 22 ‐0.10 (0.20) ‐0.50 [‐0.62, ‐0.38] 0.78 <0.001 ‐ Normative data 1 22 ‐0.60 (0.20) ‐ 0 (1) ‐0.60 [‐0.68, ‐0.52] 0.60 <0.001 ‐ ‐ Continuous Long Term 13

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Healthy controls 1 22 ‐0.50 (0.20) 22 ‐0.20 (0.30) ‐0.30 [‐0.45, ‐0.15] 0.51 <0.001 ‐ Normative data 1 22 ‐0.50 (0.20) ‐ 0 (1) ‐0.50 [‐0.58, ‐0.42] 0.50 <0.001 ‐ WISC Digit Span ‐ Healthy controls 1 20 8.50 (2.70) 18 8.60 (3.00) ‐0.10 [‐1.92, 1.72] 0.04 0.91 ‐ ‐ Normative data 1 20 8.50 (2.70) ‐ 10 (3) ‐1.50 [‐2.68, ‐0.32] 0.50 0.01 ‐ FRM Total Score 1 20 89.4 (23.4) 18 95.8 (27.1) ‐6.40 [‐22.6, 9.78] 0.25 0.44 ‐ FRM1 score 1 20 5.00 (2.00) 18 5.20 (2.10) ‐0.20 [‐1.51, 1.11] 0.10 0.76 ‐ Penn CNBd (Z‐scores) Executive control Abstraction 1 92 ‐ 69 ‐ ‐0.20 [‐0.51, 0.12] ‐ 0.22 ‐ Attention 1 92 ‐ 69 ‐ ‐0.35 [‐0.67, ‐0.03] ‐ 0.03 ‐ Working memory 1 92 ‐ 69 ‐ ‐0.19 [‐0.61, 0.24] ‐ 0.39 ‐ Episodic memory Verbal memory 1 92 ‐ 69 ‐ ‐0.25 [‐0.65, 0.15] ‐ 0.23 ‐ Facial memory 1 92 ‐ 69 ‐ ‐0.32 [‐0.68, 0.04] ‐ 0.08 ‐ Spatial memory 1 92 ‐ 69 ‐ ‐0.35 [‐0.72, 0.01] ‐ 0.06 ‐ Complex cognition Verbal reasoning 1 92 ‐ 69 ‐ ‐0.53 [‐0.87, ‐0.19] ‐ 0.002 ‐ Non‐verbal reasoning 1 92 ‐ 69 ‐ ‐0.52 [‐0.83, ‐0.22] ‐ 0.001 ‐ Spatial processing 1 92 ‐ 69 ‐ ‐0.64 [‐0.99, ‐0.29] ‐ <0.001 ‐ Social cognition Emotion identification 1 92 ‐ 69 ‐ ‐0.28 [‐0.64, 0.09] ‐ 0.13 ‐ Emotion differentiation 1 92 ‐ 69 ‐ ‐0.22 [‐0.59, 0.14] ‐ 0.23 ‐ Age differentiation 1 92 ‐ 69 ‐ ‐0.24 [‐0.61, 0.14] ‐ 0.21 ‐ DIALYSIS Intelligence Full‐Scale IQ ‐ Healthy controls 1 12 75.5 (12.2) 12 105 (10.3) ‐29.5 [‐38.5, ‐20.5] 2.61 <0.001 ‐ ‐ Normative data 2 23 83.8 (14.6) ‐ 100 (15) ‐16.2 [‐33.2, 0.86] 1.08 0.06 87 Verbal IQ ‐ Healthy controls 1 12 76.7 (6.50) 12 94.9 (6.00) ‐18.2 [‐23.2, ‐13.2] 1.52 <0.001 ‐ ‐ Normative data 2 23 83.9 (12.4) ‐ 100 (15) ‐14.1 [‐33.2, 4.89] 0.94 0.15 92 Performance IQ ‐ Healthy controls 1 12 73.8 (10.1) 12 94.9 (10.1) ‐21.1 [‐29.2, ‐13.0] 2.09 <0.001 ‐ ‐ Normative data 2 23 84.4 (14.1) ‐ 100 (15) ‐15.5 [‐37.3, 6.21] 1.03 0.16 93 Academic achievement WRAT scores ‐ Reading Healthy controls 1 26 90.0 (4.00) 26 100 (3.00) ‐10.0 [‐11.9, ‐8.08] 0.82 <0.001 ‐ Normative data 1 26 90.0 (4.00) ‐ 100 (15) ‐10.0 [‐11.5, ‐8.46] 0.67 <0.001 ‐ ‐ Arithmetic Healthy controls 1 26 89.0 (4.00) 26 92.0 (3.00) ‐3.00 [‐4.92, ‐1.08] 0.39 0.002 ‐ Normative data 1 26 89.0 (4.00) ‐ 100 (15) ‐11.0 [‐12.5, ‐9.46] 0.73 <0.001 ‐ ‐ Spelling Healthy controls 1 26 85.0 (4.00) 26 90.0 (3.00) ‐5.00 [‐6.92, ‐3.08] 0.14 <0.001 ‐ Normative data 1 26 85.0 (4.00) ‐ 100 (15) ‐15.0 [‐16.5, ‐13.5] 1.00 <0.001 ‐ TONI‐2 percentiles 1 26 27.0 (4.00) 26 32.0 (5.00) ‐5.00 [‐7.46, ‐2.54] 0.48 <0.001 ‐ Cognitive development Bayley/McCarthy 1 16 67.6 (17.3) ‐ 100 (16) ‐32.4 [‐40.9, ‐23.9] 1.94 <0.001 ‐ 14

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Developmental Scalesb TRANSPLANT RECIPIENTS Intelligence Full‐Scale IQ ‐ Healthy controls 2 18 75.5 (16.6) 32 109 (17.2) ‐29.4 [‐53.9, ‐4.77] 1.98 0.02 78 ‐ Normative data 7 153 88.3 (16.9) ‐ 100 (15) ‐11.2 [‐17.8, ‐4.50] 0.75 0.001 85 Verbal IQ ‐ Healthy controls 0 0 ‐ 0 ‐ ‐ ‐ ‐ ‐ ‐ Normative data 5 135 93.4 (18.2) ‐ 100 (15) ‐4.06 [‐11.1, 3.03] 0.27 0.26 85 Performance IQ ‐ Healthy controls 0 0 ‐ 0 ‐ ‐ ‐ ‐ ‐ ‐ Normative data 5 135 86.9 (19.6) ‐ 100 (15) ‐10.5 [‐16.8, ‐4.13] 0.70 0.001 78 WJIE scores ‐ Full‐scale Healthy controls 1 35 85.0 (26.0) 35 107 (10.0) ‐22.0 [‐31.2, ‐12.8] 1.12 <0.001 ‐ Normative data 1 35 85.0 (26.0) ‐ 100 (15) ‐15.0 [‐23.6, ‐6.39] 1.00 <0.001 ‐ ‐ Verbal ability Healthy controls 1 35 97.0 (25.0) 35 110 (13.0) ‐13.0 [‐22.3, ‐3.66] 0.65 0.006 ‐ Normative data 1 35 97.0 (25.0) ‐ 100 (15) ‐3.00 [‐11.3, 5.28] 0.20 0.48 ‐ ‐ Thinking ability Healthy controls 1 35 88.0 (28.0) 35 107 (10.0) ‐19.0 [‐28.9, ‐9.15] 0.90 <0.001 ‐ Normative data 1 35 88.0 (28.0) ‐ 100 (15) ‐12.0 [‐21.3, ‐2.72] 0.80 0.01 ‐ ‐ Cognitive efficiency Healthy controls 1 35 82.0 (25.0) 35 103 (13.0) ‐21.0 [‐30.3, ‐11.7] 0.96 <0.001 ‐ Normative data 1 35 82.0 (25.0) ‐ 100 (15) ‐18.0 [‐26.3, ‐9.72] 1.20 <0.001 ‐ WISC‐IV scores ‐ Verbal Comprehension Healthy controls 1 12 82.4 (16.6) 9 ‐ ‐ ‐ >0.05e ‐ Normative data 1 12 82.4 (16.6) ‐ 100 (15) ‐17.6 [‐27.0, ‐8.21] 1.17 <0.001 ‐ ‐ Perceptual Reasoning Healthy controls 1 12 81.8 (17.4) 9 100 (no SD) ‐18.2 ‐ >0.05e ‐ Normative data 1 12 81.8 (17.4) ‐ 100 (15) ‐18.2 [‐28.0, ‐8.36] 1.21 <0.001 ‐ ‐ Working Memory Healthy controls 1 12 80.1 (12.3) 9 92.0 (17.8) ‐11.9 [‐25.5, 1.65] 0.78 0.09 ‐ Normative data 1 12 80.1 (12.3) ‐ 100 (15) ‐19.9 [‐26.9, ‐12.9] 1.33 <0.001 ‐ ‐ Processing Speed Healthy controls 1 12 80.8 (13.9) 9 96.0 (16.5) ‐15.2 [‐28.5, ‐1.86] 1.00 0.03 ‐ Normative data 1 12 80.8 (13.9) ‐ 100 (15) ‐19.2 [‐27.1, ‐11.3] 1.28 <0.001 ‐ KABC 1 12 94.5 (6.50) ‐ 100 (15) ‐5.50 [‐14.5, 3.51] 0.37 0.23 ‐ CFIT 1, Sum 1 (overall) 1 12 94.5 (12.2) 12 100 (24) ‐5.40 [‐20.6, 9.83] 0.29 0.49 ‐ CFIT 1, Sum 3 (fluid) 1 15 98.3 (11.1) 15 100 (24) ‐1.70 [‐15.1, 11.7] 0.09 0.80 ‐ Academic achievement Single Word Reading ‐ Healthy controls 2 48 90.9 (10.7) 45 99.9 (8.13) ‐7.06 [‐8.44, ‐5.68] 0.95 <0.001 0

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‐ Normative data 2 48 90.9 (10.7) ‐ 100 (15) ‐9.31 [‐16.7, ‐1.90] 0.62 0.01 54 Mathematics ‐ Healthy controls 2 48 87.1 (10.3) 45 98.4 (11.0) ‐10.0 [‐11.4, ‐8.65] 1.06 <0.001 0 ‐ Normative data 2 48 87.1 (10.3) ‐ 100 (15) ‐12.0 [‐13.0, ‐11.1] 0.80 <0.001 0 Spelling ‐ Healthy controls 2 48 89.7 (9.10) 45 99.4 (7.85) ‐11.1 [‐22.5, 0.34] 1.14 0.06 65 ‐ Normative data 2 48 89.7 (9.10) ‐ 100 (15) ‐9.20 [‐11.2, ‐7.25] 0.61 <0.001 6 ‐ Total Achievement Healthy controls 1 12 83.7 (17.3) 9 103 (20.2) ‐19.1 [‐35.5, ‐2.67] 1.03 0.02 ‐ Normative data 1 12 83.7 (17.3) ‐ 100 (15) ‐16.3 [‐26.1, ‐6.51] 1.09 0.001 ‐ TONI‐2 scores 1 36 35.0 (5.00) 36 56.0 (6.00) ‐21.0 [‐23.6, ‐18.5] 3.80 <0.001 ‐ Peabody scores ‐ Reading 1 20 47.8 (16.0) 18 44.7 (10.6) 3.10 [‐5.45, 11.7] 0.23 0.48 ‐ ‐ Mathematics 1 20 46.3 (13.4) 18 42.8 (11.7) 3.50 [‐4.48, 11.5] 0.28 0.39 ‐ ‐ General Information 1 20 39.5 (16.5) 18 42.6 (16.9) ‐3.10 [‐13.7, 7.54] 0.19 0.57 ‐ Attention NEPSY 1 33 ‐0.21 (0.39) ‐ 0 (1) ‐0.21 [‐0.34, ‐0.08] 0.21 0.002 ‐ NEPSY‐II scores ‐ Auditory Attention Healthy controls 1 49 9.60 49 10.4 ‐0.80 ‐ >0.05f ‐ Normative data 1 49 9.60 ‐ 10 (3) ‐0.40 0.13 ‐ ‐ Executive function BRIEF (T‐scores) ‐ Behavior Regulation Healthy controls 1 9 48.3 (6.40) 9 45.3 (6.50) 3.00 [‐2.96, 8.96] 0.47 0.32 ‐ Normative data 1 9 48.3 (6.40) ‐ 50 (10) ‐1.70 [‐5.88, 2.48] 0.17 0.43 ‐ ‐ Metacognition Healthy controls 1 9 61.4 (16.3) 9 46.7 (6.40) 14.7 [3.26, 26.1] 1.19 0.01 ‐ Normative data 1 9 61.4 (16.3) ‐ 50 (10) 11.4 [0.75, 22.1] 0.11 0.04 ‐ ‐ Global Executive Healthy controls 1 9 55.8 (12.1) 9 45.7 (5.70) 10.1 [1.36, 18.8] 1.07 0.02 ‐ Normative data 1 9 55.8 (12.1) ‐ 50 (10) 5.80 [‐2.11, 13.7] 0.58 0.15 ‐ VANAT scores ‐ Auditory verbal (#) 1 20 5.07 20 7.89 ‐2.82 ‐ <0.05g ‐ ‐ Visual verbal (#) 1 20 5.87 20 7.92 ‐2.05 ‐ <0.05g ‐ ‐ Auditory written (#) 1 20 5.12 20 7.68 ‐2.56 ‐ <0.05g ‐ ‐ Visual written (#) 1 20 5.64 20 7.90 ‐2.26 ‐ <0.05g ‐ NEPSY‐II scores ‐ Auditory Attention and Response Set Healthy controls 1 49 8.70 49 10.0 ‐1.30 ‐ <0.05f ‐ Normative data 1 49 8.70 ‐ 10 (3) ‐1.30 0.43 ‐ ‐ Language NEPSY 1 33 ‐0.18 (0.13) ‐ 0 (1) ‐0.18 [‐0.23, ‐0.14] 0.18 <0.001 ‐ NEPSY‐II scores

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‐ Speeded Naming Healthy controls 1 49 8.20 49 9.85 ‐1.65 ‐ <0.05f ‐ Normative data 1 49 8.20 ‐ 10 (3) ‐1.80 0.60 ‐ ‐ ‐ Instructions Healthy controls 1 49 7.10 49 10.1 ‐3.00 ‐ <0.001f ‐ Normative data 1 49 7.10 ‐ 10 (3) ‐2.90 0.97 ‐ ‐ Memory WRAML scores ‐ Verbal Memory Healthy controls 1 9 88.8 (11.0) 9 101 (19.5) ‐11.9 [‐26.5, 2.73] 0.77 0.11 ‐ Normative data 1 9 88.8 (11.0) ‐ 100 (15) ‐11.2 [‐18.4, ‐4.01] 0.75 0.002 ‐ ‐ Visual Memory Healthy controls 1 9 88.7 (8.80) 9 86.7 (11.0) 2.00 [‐7.20, 11.2] 0.20 0.67 ‐ Normative data 1 9 88.7 (8.80) ‐ 100 (15) ‐11.3 [‐17.1, ‐5.55] 0.75 <0.001 ‐ ‐ Screening Memory Healthy controls 1 9 86.6 (9.40) 9 92.7 (14.2) ‐6.10 [‐17.2, 5.03] 0.51 0.28 ‐ Normative data 1 9 86.6 (9.40) ‐ 100 (15) ‐13.4 [‐19.5, ‐7.26] 0.89 <0.001 ‐ NEPSY 1 33 ‐0.38 (0.22) ‐ 0 (1) ‐0.38 [‐0.46, ‐0.31] 0.38 <0.001 ‐ NEPSY‐II scores ‐ Memory for Designs Healthy controls 1 49 8.70 49 9.70 ‐1.00 ‐ >0.05f ‐ Normative data 1 49 8.70 ‐ 10 (3) ‐1.30 0.43 ‐ ‐ ‐ Memory for Faces Healthy controls 1 49 8.20 49 9.00 ‐0.80 ‐ >0.05f ‐ Normative data 1 49 8.20 ‐ 10 (3) ‐1.80 0.60 ‐ ‐ ‐ Word List Inference Healthy controls 1 49 8.00 49 10.2 ‐2.20 ‐ <0.01f ‐ Normative data 1 49 8.00 ‐ 10 (3) ‐2.00 0.67 ‐ ‐ Social cognition NEPSY‐II scores ‐ Affect Recognition Healthy controls 1 49 8.10 49 10.3 ‐2.20 ‐ <0.001f ‐ Normative data 1 49 8.10 ‐ 10 (3) ‐1.90 0.63 ‐ ‐ Visuomotor skills NEPSY 1 33 ‐0.47 (0.26) ‐ 0 (1) ‐0.47 [‐0.97, 0.03] 0.47 0.07 ‐ NEPSY‐II scores ‐ Design Copying Healthy controls 1 49 6.10 49 9.10 ‐3.00 ‐ <0.001f ‐ Normative data 1 49 6.10 ‐ 10 (3) ‐3.00 1.00 ‐ ‐ ‐ Geometric Puzzles Healthy controls 1 49 7.90 49 9.90 ‐2.00 ‐ <0.01f ‐ Normative data 1 49 7.90 ‐ 10 (3) ‐2.10 0.70 ‐ ‐ ‐ Visuomotor Precision Healthy controls 1 49 7.30 49 9.80 ‐2.50 ‐ <0.001f ‐ Normative data 1 49 7.30 ‐ 10 (3) ‐2.70 0.90 ‐ ‐

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TABLE 2.2 Clinical outcomes – comparison between CKD stages Outcome Domains N (studies) N Mean (SD) N Mean (SD) Mean difference [95% CI] Effect size (Cohen’s d) P I2 (%) PREDIALYSIS vs DIALYSIS Intelligence Full‐Scale IQ 1 12 86.7 (7.90) 12 75.5 (12.2) 11.2 [2.98, 19.4] 1.09 0.008 ‐ Verbal IQ 1 12 88.2 (17.1) 12 76.7 (6.50) 11.5 [1.15, 21.9] 0.89 0.03 ‐ Performance IQ 1 12 79.8 (11.0) 12 73.8 (10.1) 6.00 [‐2.45, 14.5] 0.57 0.16 ‐ Cognitive development Bayley/McCarthy 1 15 90.3 (14.3) 16 67.6 (17.3) 22.7 [11.6, 33.9] 1.43 <0.001 Developmental Scalesb PREDIALYSIS vs. TRANSPLANT Intelligence Full‐Scale IQ 1 28 87.2 (17.8) 6 72.8 (20.0) 14.3 [‐2.95, 31.6] 0.76 0.10 ‐ Attention regulation Conners’ CPT ‐ Correct hits (#) 1 9 293 (44.0) 9 311 (22.0) ‐18.0 [‐50.1, 14.1] 0.52 0.27 ‐ ‐ False alarms (#) 1 9 14.0 (9.00) 9 13.0 (9.00) 1.00 [‐7.32, 9.32] 0.11 0.81 ‐ ‐ Reaction times (s) 1 9 0.47 (0.10) 9 0.38 (0.72) 0.09 [‐0.38, 0.56] 0.18 0.71 ‐ ‐ Discrimination (Z‐scores) 1 9 2.19 (1.29) 9 0.62 (1.55) ‐0.76 [‐1.97, 0.45] 1.05 0.22 ‐ Executive function PASAT, ChiPASAT (Z‐scores) 1 9 ‐0.07 (1.42) 9 ‐0.41 (0.62) 0.34 [‐0.67, 1.35] 0.31 0.51 ‐ VANAT scores ‐ Auditory verbal (#) 1 20 4.56 20 5.07 ‐0.51 ‐ <0.05g ‐ ‐ Visual verbal (#) 1 20 4.65 20 5.87 ‐1.22 ‐ <0.05g ‐ ‐ Auditory written (#) 1 20 5.01 20 5.12 ‐0.11 ‐ <0.05g ‐ ‐ Visual written (#) 1 20 4.78 20 5.64 ‐0.86 ‐ <0.05g ‐ TRANSPLANT vs. DIALYSIS Intelligence Full‐Scale IQ 1 13 103 (12.0) 11 92.9 (16.9) 10.1 [‐1.81, 22.0] 0.69 0.10 ‐ Verbal IQ 1 13 103 (13.5) 11 91.6 (16.6) 11.4 [‐0.88, 23.6] 0.75 0.07 ‐ Performance IQ 1 13 103 (14.4) 11 96.0 (17.4) 7.08 [‐5.86, 20.0] 0.44 0.28 ‐ Academic achievement WJ‐R scores ‐ Reading 1 13 16.4 (7.66) 11 15.6 (7.70) 0.77 [‐5.40, 6.94] 0.10 0.81 ‐ ‐ Mathematics 1 13 16.1 (7.78) 11 13.8 (5.82) 2.34 [‐3.11, 7.79] 0.33 0.40 ‐ ‐ Written 1 13 16.2 (9.05) 11 11.2 (7.18) 5.00 [‐1.50, 11.5] 0.61 0.13 ‐ WRAT scores ‐ Reading 1 36 93.0 (3.00) 26 90.0 (4.00) 3.00 [‐1.18, 4.82] 0.85 0.001 ‐ ‐ Arithmetic 1 36 88.0 (3.00) 26 89.0 (4.00) ‐1.00 [‐2.82, 0.82] 0.28 0.28 ‐ ‐ Spelling 1 36 91.0 (3.00) 26 85.0 (4.00) 6.00 [4.18, 7.82] 0.65 <0.001 ‐ TONI‐2 percentiles 1 36 35.0 (5.00) 26 27.0 (4.00) 8.00 [5.76, 10.2] 0.66 <0.001 ‐

IQ: Intelligence Quotient – scoring mean 100, SD 15 (80-89 low average, 90-109 average, 110-119 high average) *Crittenden 1985: used 6 outcome measures to assess full-scale IQ in patients with end-stage kidney disease (see Supp. Table 2) Bender-Gestalt: Bender Visual Motor Gestalt Test – scoring focussed on examinee’s specific difficulties and behavior (Gulleroglu 2013 – results below) ‐ CKD (n=20) – abnormal in 12 patients (60%); controls (n=18) – abnormal in 3 patients (15%); relative risk = 4.00 [95% CI: 1.33, 12.1], p=0.01 18

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‐ Transplant (n=20) – abnormal in 8 patients (40%); controls (n=18) – abnormal in 3 patients (15%); relative risk = 2.67 [95% CI: 0.82, 8.62], p=0.10 ‐ CKD (n=20) – abnormal in 12 patients (60%); transplant (n=20) – abnormal in 8 patients (40%); relative risk = 1.50 [95% CI: 0.79, 2.86], p=0.22 BRIEF: Behavior Rating Inventory of Executive Function – T scores = mean 50, SD 10 (higher scores reflect more impairment) CFIT: Culture Fair Intelligence Test - # of correct responses, or scoring mean 100, SD 24 ChiPASAT: Children’s Paced Auditory Serial Addition Task – Z-scores = mean 0, SD 1 (higher scores reflect less impairment) CKD: chronic kidney disease Conners’ CPT: Conners’ Continuous Performance Test – T-scores = mean 50, SD 10 (higher scores reflect more impairment) CPT: Continuous Performance Test – number of hits out of 20 (Fennell 1984) Digit Span: Subtest of WISC – scoring mean 10, SD 3 EOWPVT: Expressive One Word Picture Vocabulary Test – scoring mean 100, SD 15 GDS: Gordon Diagnostic System – scoring mean 100, SD 15 HRPS Category Test: Halstead-Reitan Problem Solving Category Test – scores above 41 suggest brain impairment for ages 15-45 years KABC: Kaufmann Assessment Battery for Children – scoring mean 100, SD 15 NEPSY: Finnish Neuropsychological Test Battery for Children – standard deviation scale +1 to -3 (0 to +1 for normal, -1 to -3 for increasing impairment) NEPSY-II: Finnish Neuropsychological Test Battery for Children – scoring mean 10, SD 3 NSRT: Nonverbal Selective Reminding Test – Z scores = mean 0, SD 1 (higher scores reflect less impairment) PASAT: Paced Auditory Serial Addition Test – Z-scores = mean 0, SD 1 (higher scores reflect less impairment) Peabody: Peabody Individual Achievement Test – uncertain scoring presentation by Fennell 1984 Penn CNB: Penn’s Computerized Neurocognitive Battery – scoring presentation as Z-score differences between patient cohorts TONI-2: Test of Nonverbal Intelligence, Second Edition – scoring by percentile ranks (mean 50) VANAT: Visual and Auditory Number Assay Test – scoring by number of repeated digits correctly recorded WJ-R: Woodcock-Johnson Tests of Cognitive Abilities, Revised Edition – scoring by age-equivalent scores WIAT: Wechsler Individual Achievement Test – scoring mean 100, SD 15 (80-89 low average, 90-109 average, 110-119 high average) WRAML: Wide Range Assessment of Memory and Learning – scoring mean 10, SD 3 (6.0-7.9 low average, 8.0-11.9 average, 12.0-13.9 high average) WRAT: Wide Range Achievement Test – scoring mean 100, SD 15 (80-89 low average, 90-109 average, 110-119 high average) WRMT-R: Woodcock Reading Mastery Tests-Revised – scoring mean 100, SD 15 (80-89 low average, 90-109 average, 110-119 high average) a Domains in Mirsky’s model of attention (Duquette 2008) b Cognitive development - scoring mean 100, SD 16 c Two studies used the EOWPVT, but results were not reported in one study (Bawden 2004) d Results reported as Z-score differences in Hartung 2016 e WISC-IV scores for Verbal Comprehension and Perceptual Reasoning Indices not given in Johnson 2013; p-values as reported in study f p-values reported by Haavisto 2012 g p-values reported by Gulleroglu 2013

Supplemental material is neither peer-reviewed nor thoroughly edited by CJASN. The authors alone are responsible for the accuracy and presentation of the material. NB// Missing data in: ‐ El-Shazly 2010: IQ scores ‐ Fennell 1990: only p-values reported for all outcomes ‐ Gipson 2006: IQ scores ‐ Gulleroglu: Cancellation Test results ‐ Haavisto 2012: SD for all outcomes ‐ Hartung 2016: Z-scores for all outcomes ‐ Hartung 2014: mean and SD for all outcomes ‐ Hulstijn-Dirkmaat 1992: SD not reported for all outcomes ‐ Mendley 2015: mean and SD for all outcomes) ‐ Mendley 1999: results for the Stroop Color-Word Naming Test, Buschke Selective Reminding Test, Meier Visual Discrimination Test, Grooved Pegboard Test, and the Trail-making Test ‐ Rasbury 1983: results for the Free Recall Memory Task

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Supplementary Figure 1.1: Single Word Reading Accuracy ‐ Predialysis vs normative data

Supplementary Figure 1.2: Reading Comprehension ‐ Predialysis vs normative data

Supplementary Figure 1.3: Mathematics ‐ Predialysis vs normative data

Supplementary Figure 1.4: Spelling ‐ Predialysis vs normative data

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Supplementary Table 4: Funnel plots (full-scale IQ)

Comparison against health controls Comparison against normative population data Mild-to-moderate stage CKD1

Dialysis

Transplant

1CKD: chronic kidney disease

Author list Kerry Chen1,2, Madeleine Didsbury1,2, Anita van Zwieten1,2, Martin Howell1,2, Siah Kim1, Allison Tong1,2, Kirsten Howard², Natasha Nassar3, Belinda Barton4, Suncica Lah5, Jennifer Lorenzo6, Giovanni Strippoli7, Suetonia Palmer8, Armando Teixeira-Pinto2, Fiona Mackie9, Steven McTaggart10, Amanda Walker11, Tonya Kara12, Jonathan C. Craig1,2, Germaine Wong1,2,13

1Centre for Kidney Research, The Kids Research Institute, The Children’s Hospital at Westmead, Sydney, Australia 2Sydney School of Public Health, The University of Sydney, Sydney, Australia 3Menzies Centre for Health Policy, Sydney School of Public Health, The University of Sydney, Sydney, Australia 4Children’s Hospital Education Research Institute, The Children’s Hospital at Westmead, Sydney, Australia 5School of Psychology, The University of Sydney, Sydney, Australia, and the Australian Research Council Centre of Excellence in Cognition and its Disorders, Macquarie University, Sydney, Australia 6Institute for Neuroscience and Muscle Research, The Children’s Hospital at Westmead, Sydney, Australia 7Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy 8Department of Medicine, University of Otago, Christchurch, New Zealand 9Department of Renal Medicine, Sydney Children’s Hospital at Randwick, Sydney, Australia 10Child and Adolescent Renal Service, Children’s Health Queensland, Brisbane, Australia 11Department of Renal Medicine, The Royal Children’s Hospital, Melbourne, Australia 12Department of Nephrology, Starship Children’s Hospital, Auckland, New Zealand 13Centre for Transplant and Renal Research, Westmead Hospital, Sydney, Australia