The central nervous system in childhood chronic kidney disease

Investigations into neurodevelopmental outcomes in CKD pediatric cohorts were sparked by seminal brain imaging studies of the early 1980s, which found several cortical abnormalities in this population. Researchers utilized computed tomography (CT) scans and magnetic resonance imaging (MRI) to verify the neuroanatomical abnormalities such as cerebral atrophy and infarcts in children with ESRD [3‐6]. Cerebral atrophy has been documented in 12–23% of children with ESRD [4, 5, 7]. Research has focused on certain disease groups at greater risk for CNS dysfunction than the general CKD population, including cohorts of congential nephrotic syndrome, cystinosis and Lowe syndrome. Valanne et al. [7] reported the MRI findings of 33 patients, comprised mostly of children with congenital nephrotic syndrome between 6 and 11 years of age, who received a kidney transplant prior to 5 years of age [7]. Results indicated that 18 of 33 (54%) patients had chronic infarct lesions mostly within the periventricular white matter. Comparable to previous findings, cerebral atrophy was found in five of 33 (15%) patients [5, 7]. Evidence of white matter lesions in this sample of patients with congenital nephrotic syndrome was highly correlated with transplantation at a later age (P<0.05), longer duration of dialysis (P<0.02), and a history of hemodynamic crisis (P<0.03) [7]. Findings by Nichols et al. [8] on pediatric patients with cystinosis from infancy showed that ten of 11 (91%) patients had cortical atrophy. Case studies on CNS and renal involvement of patients with Lowe syndrome have also suggested the presence of cerebral atrophy and seizure disorders [9]. In summary, children with CKD are at risk for central nervous system (CNS) structural abnormalities of atrophy and infarcts. These lesions may be observed with greater frequency in populations at risk for coagulation disorders such as congenital nephrotic syndrome and among those with a history of hypertensive crisis. The overall risk for CNS structural abnormalities can only be estimated based on currently published data for children with ESRD. Additional research into the risks for CNS structural abnormalities in children with less severe CKD and a broader scope of the general CKD population will be necessary for advances in this field.

In addition to structural abnormalities, children with CKD have also shown deficits in cerebral and peripheral nerve conduction. Measurement techniques in this area include electroencephalography (EEG) measuring cortical electrical activity; brain stem evoked responses measuring brainstem response to stimuli in both timing and intensity; and peripheral nerve conduction assessing peripheral nerve function. Four reports of EEG findings have been published since 1990 in the pediatric CKD literature. In a report on patients with CKD from infancy, results identified unspecified EEG abnormalities in six of 14 (42%) patients but no abnormalities were found with brainstem auditory evoked potentials [4]. Similar rates of EEG abnormalities (12 of 33, 36%) have been reported for patients after renal transplant, all of whom had ischemic watershed zone lesions on MRI images of the CNS [5]. Hurkx et al. [10] also evaluated 22 children with CKD. Brainstem conduction in the auditory pathway was within normal limits and did not differ between the peritoneal dialysis and chronic renal insufficiency (CRI) subgroups. However, results did suggest the possibility of delayed myelination or synaptogenesis of the somatosensory pathway in young children with CKD regardless of renal replacement therapy [10]. This finding was explained by deficits in cortical conduction via the thalamus as measured by high interpeak somatosensory evoked potential latencies, which suggests that earlier onset of CKD pathology could hinder maturation of the myelin sheath in the somatosensory cortex. Contemporary estimates of the frequency of seizure disorders among children with CKD are not known.

Research on adults with CKD expands our understanding of the relationship between severity of kidney disease and electrophysiology. A progressive slowing of EEG waves is correlated with progressive elevation in serum creatinine [11] (see Fig. 1). Additional evaluation of the relationship between evoked potential and the severity of anemia of CKD confirms a slow and diminished intensity of CNS response to stimuli with anemia. This CNS function improves with correction of anemia with erythropoietin therapy in adults with CKD. Similar data in pediatric patients are not available [11‐15].

Assessment of peripheral nerve conduction function in children is supported by long-standing documentation of abnormalities in this area in adults with CKD. A single study has measured peripheral nerve conduction using the median nerve in ten children on hemodialysis between the ages of 9 and 19 years. Comparing their performance to age- and gender-matched controls, abnormal peripheral conduction velocities were documented in three of ten (30%) children [16].

In addition to the assessment of CNS structure and nerve conduction, the functional status of the developing child is assessed though neuropsychological testing and educational achievement. Cross-sectional studies of children with CKD suggested that there is increased risk for delays in neurocognitive development, particularly for toddlers [17‐19] and children with end-stage renal disease (ESRD) [17‐23]. Unfortunately, no large-scale, prospective neurocognitive evaluation of this health-challenged group has been done to allow for an accurate prediction of the incidence, prevalence, and magnitude of developmental problems. The studies to date have used modestly sized cohorts to examine general neurocognitive functions as well as more specific neurocognitive domains, including attention, executive function, language, visual-spatial abilities and memory (see Table 1).

There are relatively few studies examining the academic achievement and school functioning of children with CKD. When reviewing the cognitive functions summarized above, one might expect limitations in math and reading, based on difficulties with executive functioning and memory domains. In general, the available studies suggest that transplant recipients outperform dialysis-dependent patients in the broad academic areas of reading, math, and language [30]. Brouhard et al. [23] reported findings showing the combined ESRD group (transplant and dialysis) had lower achievement scores than their sibling controls in spelling, math, and reading. In contrast, Bawden et al. [29] demonstrated that children with ESRD showed no group differences on various measures of basic reading, spelling, math, reading comprehension, and phonological processing when compared with their sibling controls.

The educational status of children with CKD will typically reflect the cognitive abilities and adaptive functioning of the student. Just as one can find means to perform at peer level with a physical disability, the adaptive capabilities of a child may allow school functioning beyond the predicted level based on neuropsychologic testing. In North America and Europe, 79–94% of children with CKD receive their education in regular educational settings, while 13–15% received special education services not related to visual or hearing impairments [5, 26]. Findings from the cohort by Qvist and co-workers suggested that ten of 13 (77%) patients receiving special education services had CNS infarcts [5]. The rates of special education service provision for children with CKD are equivalent to national rates among the general population [34]. Given the evidence for neuropsychological impairment across the CKD spectrum, however, these rates may represent an underestimate of the number of children with CKD who may actually require special education services to perform optimally in the school setting [18]. Further research should address this need, while routine clinical care should include a thorough psychoeducational screening and ongoing monitoring of school performance in this population.

Educational attainment and employment have been examined in follow up investigations of childhood ESRD cohorts. Neuropsychological impairment beginning in children with CKD has been shown to persist into adulthood [29, 35]. A Dutch study found adult survivors of childhood onset ESRD have Verbal IQ, Performance IQ, and Full Scale IQ to be 9.7, 9.2, and 10.4 points (P values <0.0001) lower than controls, respectively [35]. In addition, the educational attainment is also much lower for adults with childhood-onset ESRD compared with national population statistics [35]. A retrospective study by Broyer et al. [36] found that only 31.2% of their transplant cohort had received a high school diploma, and 68.8% had a junior high education or less. With the burden of diminished cognitive function and lower levels of education, 50–75% of adults with a functioning transplant and 25–60% of patients on dialysis are employed as adults [37]. Lower rates of employment and low occupational level are associated with dialysis rates longer than 8 years [38]. These rates vary by country, with some countries (e.g., France) showing employment rates similar to the general population [36].

A practical approach to the assessment of CNS structure and function may include CNS imaging when indicated by a history of poor cranial growth, hemodynamic instability or prolonged dialysis dependence. EEGs are indicated with a concern for seizure disorders but are not recommended for all patients. Early assessment of cognitive function for all children with severe CKD and ESRD is recommended. This assessment should include a general assessment of cognition using DQ or IQ depending on patient age. Additional testing for specific abnormalities in the domains of memory, attention, executive function and visual-spatial skills will complete the assessment for school-age children. After transplantation, a repeat evaluation may prove useful to define remaining deficits and to restructure specific educational plans. Furthermore, developmental intervention for preschool children and educational support through individual educational plans, tutoring or special classes will likely optimize the developmental and educational outcome for children with CKD.