Icard P, Hooper SR, Gipson DS, Ferris ME. Cognitive improvement in children with CKD after transplant. Pediatr Transplantation 2010: 14:887–890. © 2010 John Wiley & Sons A/S. The primary purpose of this paper was to examine the cognitive functioning of children with CKD receiving transplantation to children with CKD not receiving transplantation, and a healthy control group. The sample included six children with CKD receiving transplant, 28 children with CKD being treated conservatively, and 23 healthy controls. All participants were administered intellectual (IQ) or developmental assessments at baseline and at a one-yr follow-up. Results revealed that children with CKD who had received transplant showed a significant increase in their intellectual/developmental functioning post transplant compared to children with CKD not receiving transplant. Although their overall intellectual/developmental level was not fully normalized, when compared with the healthy control group, the change scores for the transplant group reflected over a 12 point increase, moving the group from the borderline range to the low average range of functioning. In this regard, pediatric transplantation appears to have a positive impact on the intellectual and developmental functioning of children with CKD

Ferris, Maria E.

Gipson, Debbie S.

Hooper, Stephen R.

Icard, Phil

Carolina Digital Repository

Cognitive Improvement in Children with CKD after TransplantPhil Icard1, Stephen R. Hooper1,2, Debbie S. Gipson3,4, and Maria E. de Ferris31Center for Development and Learning, Carolina Institute for Developmental Disabilities,University of North Carolina School of Medicine2Departments of Psychiatry and Pediatrics, University of North Carolina School of Medicine3University of North Carolina Kidney Center4University of MichiganChildren with end-stage kidney disease (ESKD) requiring dialysis and subsequenttransplantation are at risk for neurodevelopmental delays and deficits. Lower scores onmeasures of IQ and academic achievement, as well as in specific cognitive domains oflanguage, visual-spatial perception, attention, memory, and executive function have beendocumented by previous research [1,2]. These deficits have been corroborated with imagingand electrophysiological investigations showing periventricular white matter lesions, corticalatrophy, slower peripheral nerve conduction, and delayed myelination of the somatosensorycortex [3]. Slickers and colleagues found that younger age of onset, longer duration ofkidney disease, and increased disease severity were associated with lower cognitivefunctioning [4]. Although the relationship between kidney function and cognitive abilities isnot linear, pediatric populations progressing to ESRD and dialysis dependence appear to beat increased risk for neurodevelopmental, intellectual, and related cognitive deficits [5].Few studies have examined the impact of kidney transplant on cognitive function, and theavailable evidence is inconclusive. Lawry and colleagues [6] compared the IQ scores of 9children receiving dialysis, 2 children treated conservatively, and 13 transplant recipients. Ahigher mean IQ was found in the transplanted group compared to the dialysis group,although mean scores for both groups fell largely in the average range. Conversely,Brouhard et al. [7] conducted a cross-sectional study comparing 26 children with transplantto 26 dialysis dependent children and found no overall differences in intellectualfunctioning. Even fewer studies have followed children with ESKD longitudinally in orderto assess the cognitive impact of receiving a kidney transplant. Mendley and Zelko [8] foundmental decision speed and sustained attention to be improved after transplant in a sample ofnine children with ESKD. Despite the relatively limited evidence for neurocognitiveimprovement after pediatric kidney transplant, a neurobiological model would suggest thatimproving kidney filtration should decrease the amount of neurotoxic exposure to the brainwhich, in turn, may improve neuronal myelination and synaptic development as well asoverall neurological efficiency.The current study seeks to examine the pre- and post-transplant neurocognitive function in asmall cohort of children with chronic kidney disease (CKD). It was hypothesized thatcompared to a healthy control sample and pediatric CKD patients being treatedconservatively, children receiving transplants would show significant increases inintellectual function during post-transplant follow-up.Corresponding Author: Stephen R. Hooper, Ph.D., Clinical Center for the Study of Development and Learning (CDL), CB# 7255,Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, North Carolina27599-7255, stephen.hooper@cdl.unc.edu.NIH Public AccessAuthor ManuscriptPediatr Transplant. Author manuscript; available in PMC 2011 November 1.Published in final edited form as:Pediatr Transplant. 2010 November ; 14(7): 887–890. doi:10.1111/j.1399-3046.2010.01359.x.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptMethodsParticipantsSix children with transplant, 20 children with CKD (no transplant), and 23 healthy childrenwere recruited as part of a larger investigation of neurocognitive function in pediatric CKD.Baseline neuropsychological functioning has been reported previously for this cohort [2,4].Patients with CKD were recruited from a university nephrology clinic; healthy controlsubjects were recruited from the catchement area of the surrounding community. Inclusioncriteria for CKD patients were: 1) 0 to 18 years of age; and 2) Schwartz GFR < 90 ml/min/1.73m2 or dialysis dependency for 3 months. Exclusion criteria were: 1) no prior kidneytransplant; and 2) no history of comorbid conditions associated with CNS anomalies. TheCKD group (no transplant) was comprised of children with moderate/severe CKD ordialysis dependency. Seven children were classified as having moderate kidney disease(GFR = 30-59 ml/min/1.73m2), 4 children were severe (GFR = 15-29 ml/min/1.73m2), and15 children had progressed to end-stage kidney disease (GFR < 15 ml/min/1.73m2) or wereon dialysis. Inclusion criteria for the healthy control group were: 1) birth to 18 years of age;2) no history of chronic health conditions, developmental disorders, head trauma,neurological illness, or medication usage other than multivitamins. Maternal education wasobtained as a measure of socioeconomic status in children with CKD and the healthy controlgroup. Maternal education was coded as follow: 1 – less than high school diploma; 2 – highschool diploma or GED; 3 – two year vocational degree; 4 – four year college degree; and 5– graduate or professional degree.The CKD-transplant group was 10.7 years of age (range 5.3 – 17.9) with an average timebetween visits of 12.8 months. Post-transplant evaluation occurred on average 6.3 monthsafter transplant. The CKD-transplant group was 50% male, 33.3% Caucasian, and 75%right-handed. The average maternal education for the CKD-transplant group was 2.5. TheCKD-no transplant group was 7.8 years of age (range 0.2 – 16.2) with an average timebetween visits of 10.9 months. This group was 65.0% male, 40% Caucasian, and 83% right-handed. The average maternal education for the CKD-no transplant group was 2.8. Thehealthy control group was 10.3 years of age (range 1.5 – 18.4) with an average time betweenvisits of 11.0 months. This group was 52% male, 87% Caucasian, and 94% right-handed.The average maternal education for the healthy control group was 4.4. Upon entry to thestudy, the baseline assessment was considered Time 1; Time 2 was considered either thesecond visit for the CKD–no transplant and control groups, or the post-transplant visit forthe CKD-transplant group.ProceduresPatients and control subjects received IQ or developmental testing at baseline andapproximately one year after baseline. Post transplant evaluation was given at a minimumthree months post transplant. The Mullen Scales of Early Learning (MSEL) wasadministered to children five years of age or younger (n = 17). The Wechsler AbbreviatedScale of Intelligence (WASI) was administered to children and adolescents 6 to 18 years ofage (n = 40). The MSEL and WASI provided measures of general developmental andintellectual functioning, respectively. IQ and composite scores have a mean of 100 and astandard deviation of 15. Across all of the groups, none of the participants moved from theMullen at Time 1 to the WASI at Time 2, thus limiting possible variance secondary tochanges in testing procedures. This study was reviewed and approved by the University ofNorth Carolina Institutional Review Board.Icard et al. Page 2Pediatr Transplant. Author manuscript; available in PMC 2011 November 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptData AnalysisData were examined using SPSS 14.0 software. Any significant differences in demographicvariables were covaried in subsequent analyses. Change in developmental and/or intellectualfunctioning over time was calculated as: (Time 2/Posttransplant Visit – Time 1). AnANOVA was used to determine if children receiving transplant showed a greater increasecognitive functioning over time compared to children with CKD not receiving transplant andhealthy controls. An additional chi-square analysis examined the effect size magnitude ofcognitive improvement from baseline measured via Cohen's d. Degree of improvement wasclassified as small (Cohen's d ≥ 0.2), moderate (Cohen's d ≥ 0.5), and large (Cohen's d ≥0.8).ResultsPreliminary AnalysesChildren receiving transplant, children with CKD not receiving transplant, and the healthycontrol group did not differ on age, F(2,46) = 1.39, p = ns, gender (χ2 = 0.86, p = ns),handedness (χ2 = 1.62, p = ns), or time between visits F (2,46) = 0.61, p = ns. A significantdifference was found for race (χ2 = 15.93, p > .05) and maternal education F(2, 40) = 19.03,p < .001). Covarying race and maternal education did not change the outcome of the analysisand were, therefore, not covaried in the final analysis due loss of power from missing data.Cognitive ImprovementAcross the three groups, a significant difference was found between Time 1 and Time 2assessments, F (2,54) = 4.68, p < .05. Means and standard deviations are presented in Table1. Post-hoc analysis using a Bonferonni correction for multiple comparisons showed thatchildren receiving transplants had a significant increase in intellectual functioning comparedto children with CKD not receiving transplant (p < .05). The effect size for the differencebetween these two groups was large (Cohen's d = 1.12). Children receiving transplant hadmean change in IQ of 12.17 points (SD = 12.02). Children with CKD not receivingtransplant had a mean change in IQ of -3.45 points (SD = 15.53). The healthy control grouphad a mean change in IQ of 3.00 points (SD = 5.68). Although children receiving transplanthad approximately a ten-point greater increase in IQ than the healthy control group thisdifference was not significant; however, the effect size was large (Cohen's d = 0.98) andgreater than would be expected given normal development.Conversely, analysis of the magnitude of cognitive improvement (i.e., effect size) betweenthe three groups was not significant (χ2 = 6.99, p = ns.). However, for the CKD groupreceiving transplant, 33% had cognitive increases greater than or equal to two-thirds astandard deviation (≥ 12 points), 16.7% had a moderate increase (8 – 11 points), and 33.3%had a small increase (3 – 7 points). Comparatively, within the CKD group not receivingtransplant, 15.0% had a small increase, 20.0% had a moderate increase, and 5.0% had anincrease that would be considered large. For the healthy control group, 30.4% had a smallchange, 17.4 % had a moderate change, and 8.7% had large changes in cognitive function.DiscussionThe current study examined the impact of pediatric kidney transplantation on the cognitiveand developmental functioning of children with CKD. Although a relatively small samplewas examined, this one of only a few studies which examined the impact of kidneytransplant on developmental and intellectual functioning in children. In general, findingsfrom this study suggest that children with CKD receiving transplant evidenced significantimprovement in their overall cognitive function after transplant. Specifically, children withIcard et al. Page 3Pediatr Transplant. Author manuscript; available in PMC 2011 November 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptCKD receiving transplant showed approximately a 12-point increase in intellectualfunctioning, which descriptively went from the borderline range to the low average range.Although transplant did not appear to normalize developmental status or intellectualfunctioning, these findings support previous investigations espousing the overall benefits ofpediatric kidney transplantation on cognitive abilities [8]. Children with CKD not receivingtransplants showed a mild decrease in intellectual function (3 points) by their second visit,which may be related to environmental effects or, perhaps, worsening kidney function.As previously mentioned, a neurobiological model of the relationship between kidneyfunction and brain development would suggest that improving kidney filtration, andsubsequently decreasing the amount of neurotoxins in the bloodstream, would be beneficialfor brain growth and performance. Given that childhood and adolescence are important timeperiods for brain myelination and synaptic development, the potential neurocognitive impactof CKD and its associated symptoms (e.g., hypertension, anemia, uremia) is of greatconcern. The significant improvement seen in our small sample supports this model;however, it is important to note that other researchers have not found significant differencesin cognitive performance between dialysis dependent and transplant cohorts [7]. In addition,other research has suggested that cognitive improvements after transplant may be related tomultiple factors including diminished aluminum burden and better nutritional regulation [9].Over the past decades, we have acknowledged the burden of CKD and uremia on cognition,and we have provided pilot data that transplantation can reduce this burden. As we currentlymanage approximately 7,000 children with ESRD in the USA, and much larger numbersglobally [10], it will be important to continue to examine this issue, perhaps from a multi-disciplinary, multi-center, prospective investigation in an effort to more definitively addressthis question.AcknowledgmentsThis research was supported by grants from the Renal Research Institute, the Maternal Child Health Bureau(#MCJ379154A), the Administration on Developmental Disabilities (#90DD043003), and the General ClinicalResearch Centers program (RR00046) of the Division of Research Resources, National Institutes of Health.References1. Gerson AC, Butler R, Moxey-Mims M, Wentz A, Shinnar S, Lande MB. Neurocognitive outcomesin children with chronic kidney disease: Current findings and contemporary endeavors. MentalRetardation and Developmental Disabilities. 2006; 12:208–215.2. Gipson DS, Hooper SR, Duquette PJ, Wetherington CE, Stellwagen KK. Memory and executivefunctions in pediatric chronic kidney disease. Child Neuropsychology. 2006; 12:391–405.[PubMed: 16952886]3. Gipson DS, Duquette PJ, Icard PF, Hooper SR. The central nervous system in childhood chronickidney disease. Pediatric Nephrology. 2007; 22:1703–1710. [PubMed: 17072652]4. Slickers J, Duquette P, Hooper S, Gipson D. Clinical predictors of neuocognitive deficits in childrenwith chronic kidney disease. Pediatric Nephrology. 2007; 22:565–572. [PubMed: 17180361]5. Hulstijn-Dirkmaat GM, Damhuis IHW, Jetten MLJ, Koster AM, Schroder CH. The cognitivedevelopment of preschool children treated for chronic renal failure. Pediatric Neprhology. 1995;9:464–469.6. Lawry KW, Brouhard BH, Cunningham RJ. Cognitive functioning and school performance inchildren with renal failure. Pediatric Nephrology. 1994; 8:326–329. [PubMed: 7917859]7. Brouhard BH, Donaldson LA, Lawry KW, McGowan KRB, Drotar D. Cognitive functioning inchildren on dialysis and post-transplantation. Pediatric Transplantation. 2000; 4:261–267. [PubMed:11079264]Icard et al. Page 4Pediatr Transplant. Author manuscript; available in PMC 2011 November 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript8. Mendley SR, Zelko FA. Improvement in specific aspects of neurocognitive performance in childrenafter renal transplantation. Kidney International. 1999; 56:318–323. [PubMed: 10411708]9. Warady BA, Belden B, Kohaut E. Neurodevelopmental outcome of children initiating peritonealdialysis in early infancy. Pediatric Nephrology. 1999; 13:759–765. [PubMed: 10603115]10. Warady BA, Chadha V. Chronic kidney disease in children: the global perspective. PediatricNephrology. 2007; 22:1999–2009. [PubMed: 17310363]Icard et al. Page 5Pediatr Transplant. Author manuscript; available in PMC 2011 November 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptIcard et al. Page 6Table 1Composite IQ/Developmental Scores over Time (Mean = 100, SD = 15).Group Time 1 Time 2CKD – Transplant 72.83 (19.95) 85 (19.04)CKD – No Transplant 87.15 (17.78) 83.55 (23.58)Control 115.13 (16.49) 118.13 (15.13)Note. Scores represent a combination of the Mullen Early Learning Composite and the WASI Full-4 IQPediatr Transplant. Author manuscript; available in PMC 2011 November 1.

Cognitive improvement in children with CKD after transplant: Cognitive improvement in children with CKD

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Cognitive improvement in children with CKD after transplant: Cognitive improvement in children with CKD

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