Introduction 1 2 3 4 2 3 5 6 7 The purpose of this paper is to review the contemporary published literature that focuses on the neurological impact of CKD in children. Papers selected for this review have been published from 1990 to the present, and were selected to coincide with the improvements in treatment, including the diminution of aluminum exposure and availability of erythropoietin that occurred circa 1990. These studies span work in neuroimaging, electrophysiology, and neuropsychology to address central nervous system (CNS) function. We also present available studies addressing the integrity of the peripheral nervous system. Central nervous system studies Neuroimaging 8 9 10 11 11 Electrophysiology findings 11 8 8 12 5 6 13 Neuropsychology findings 1 Table 1 CKD  SD  CAPD Author/date Sample features Comparison group Findings 28 n Pre-post transplant design Mental development 20 Dialysis at pre-transplant evaluation  Improved from pre- (mean=77.0, range 50–116) to post-transplant (mean=91.4, range 50–117) 17 Conservative at pre-transplant evaluation Mean age at transplant=17.6 months Motor development  Improved from pre- (mean=68.7, range 50–86) to post-transplant (mean=85.6, range 65–109) Cognition  No change from pre- (mean=92.0) to post-transplant (mean=90.4) Overall development worse with early onset of ESRD 22 n n Cognition Mean age=13.6 years Testing at 6-month intervals  Decreased verbal ability in CKD Mean age of CKD onset=6.05 years Visual motor skills  Decreased in CKD Modality: Memory and learning  Hemodialysis (7)  Decreased in CKD and loss of function over time  Peritoneal dialysis (12) Attention  Kidney transplant (10)  No differences between CKD and controls  Conservative (27) 18 n Transplant compared with dialysis plus conservative Cognition Modality:  IQ: no differences between dialysis plus conservative (mean=92.91, SD=16.86) vs. transplant (mean=103.00, SD=11.97)  Dialysis (9)  Conservative (2)  Kidney transplant (13) r Achievement P P P 8 N=15 None Developmental screening Modality:  3 of 15 with developmental delay  Dialysis (6)  Transplant (3)  Conservative (6) 14 n None Developmental index Mean age=2.5 years Testing every 6 months  Conservative (mean=90.3, SD=14.3) greater than ESRD (mean=67.6, SD=17.3) Modality:  Dialysis (16)  Conservative (15) Verbal, perceptual performance, and quantitative scales  No change over time 19 n Pre-post transplant design Cognition (baseline only)  Full-scale IQ mean=91.6 Mean age at pre-transplant testing=14.2 years  Verbal IQ mean=91.4  Performance IQ mean=95.1 Mean age at post-transplant testing=15.8 years Attention P Pre-transplant modality: Executive functioning  Peritoneal dialysis (5) P  Hemodialysis (3)  Conservative (1) Mean age of onset of ESRD=11.9 years Memory Mean duration of ESRD prior to transplant=2.5 years P 16 n Longitudinal design Development, general Modality:  6 of 28 children below the average range at 1 year of age  CAPD at ≤3 months of age Cognition Transplant at mean age=2.1±0.8 years  Verbal IQ: 5 of 18 children below the average range at ≥4 years of age Mean age at follow-up=7.8±2.8 years (range 2.5–12.0 years)  Non-verbal IQ: 8 of 18 children below the average range at ≥4 years of age  1 child within impaired range on both verbal and non-verbal IQ 15 17 n Longitudinal design Development, general Mean age at start of dialysis=0.38 years (range 0.02–1 year)  2 of 8 school-aged children had general delays Duration of dialysis=17.3 months (range=1–59 months)  2 of 8 children <5 years of age had general delays Mean age at assessment=5.84 (range 1.58–12.00 years) Cognition  IQ: 67% in average range, and 20% in low-average range (mean=86.5, range 50–102)  Lower IQ scores for children with co-morbid diagnoses (mean=67.0) than for those with ESRD alone (mean=94.2) Attention  7 of 14 children with hyperactivity problems Social-behavioral  6 of 14 children displaying conduct problems 21 n n Cognition Mean age: 13.8±0.4 years  IQ: ESRD less than siblings Modality: 26 dialysis, 36 transplant  No difference in dialysis vs. transplant Academic achievement  ESRD less than controls for all measures of spelling, reading, and mathematics  No difference dialysis vs. transplant Correlation between age of diagnosis and academic achievement Correlation between parental education and academic achievement 11 n None Cognition Mean age at assessment=8 years (range=7–12 years)  Verbal IQ: mean=87.5  Non-verbal IQ: mean=87.5 IQ range  Low: 3/33  Low-average: 14/33  Average: 14/33  Above average: 2/33 Neuropsychological battery  No overall group deficits with attention, language, memory, or visuospatial abilities when compared with normative population Neuropsychological deficits  Attention: 8 of 33 children  Language: 2 of 33 children  Memory: 6 of 33 children  Visuospatial: 8 of 33 children Motor function  Hemiplegia: 3 of 33 children  Bilateral infarction: 1 of 33  Cerebral palsy: 1 of 33 Auditory function  2 of 33 children with moderate sensorineural hearing loss General neurocognitive function 14 14 15 16 8 15 16 11 14 15 16 17 18 19 20 21 16 16 18 21 11 16 19 22 Attention and executive function 11 19 22 22 19  P  P 11 Language 11 23 17 22 11 Visuospatial abilities 22 11 SDS Memory 22 24 11 19 Academic achievement 18 n n 18 21 21 11 16 25 Peripheral nervous system 26 27 8 8 Key variables affecting neurodevelopmental outcomes CKD is a complex disorder and, similar to other pediatric disorders, there are undoubtedly a variety of variables that contribute to the neurodevelopmental status of this population. Key variables presented here are postulates for the most part as the studies conducted since 1990 have not been adequately powered to assess multiple influential factors. 18 28 29 14  P 24 30 31 24 32 33 34 11 16 21 11 16 21 6 35 36 37 38 39 40 11 41 42 20 11 43 Conclusions Emergent findings appear to apply to three broad groups of children and adolescents: mild-to-moderate CKD, dialysis-dependent children, and transplant-dependent children. What is known about children with mild-to-moderate CKD is severely limited, with no focused studies addressing their neurodevelopmental needs. More is known about the pediatric dialysis population, with deficits in the areas of attention, language, visual-spatial abilities, and memory. However, the differentiation of problems that may relate to disease-specific variables, such as age at onset of kidney failure, anemia, and hypertension, remain relatively unknown and modestly examined at best. For the transplant-dependent group, cognitive deficits appear to persist, supporting the conclusion that the transplant does not result in complete neurocognitive “recovery.” 8 32 33 34 44