Understanding the impact of pediatric kidney transplantation on cognition: A review of the literature

Chronic kidney disease (CKD) is a relatively rare childhood disease that is associated with a wide array of medical comorbidities. Roughly half of all pediatric patients acquire CKD due to congenital anomalies of the kidneys and urinary tract, and of those with congenital disease, 50% will progress to end‐stage kidney disease (ESKD) necessitating a kidney transplantation. The medical sequelae of advanced CKD/ESKD improve dramatically following successful kidney transplantation; however, the impact of kidney transplantation on neurocognition in children is less clear. It is generally thought that cognition improves following kidney transplantation; however, our knowledge on this topic is limited by the sparsity of high‐quality data in the context of the relative rarity of pediatric CKD/ESKD.


| INTRODUC TI ON
Chronic kidney disease (CKD) is a relatively rare childhood disease that is associated with a wide array of comorbidities including metabolic acidosis, 1 cardiovascular disease, 2 anemia, 3 and neurocognitive deficits 4,5 -all of which worsen with progression of CKD to end-stage kidney disease (ESKD).Although children under 20 years of age make up less than 2% of the total ESKD population in North America, the prevalence of pediatric ESKD has increased by 32% since 1990. 6,7Approximately half of all pediatric CKD patients with congenital disease-the most common disease cause for the pediatric population-will require kidney transplantation. 8The medical sequelae of advanced CKD/ESKD improve dramatically following successful kidney transplantation; however, the impact of kidney transplantation on neurocognition in children is less clear.
In this review, we will describe neurocognition in relationship to kidney transplant (KT).Given the paucity of pediatric data on this topic, our review will include pertinent data from adult KT populations where applicable.Available neuroimaging studies in pediatric and adult KT recipients will also be discussed.Lastly, we will touch upon the complex relationship between neurocognition and adherence to medical therapy following pediatric KT.

| SUBTLE COG NITIVE DEFICITS IN E ARLY-S TAG E PED IATRI C CK D
Neurocognitive deficits have been well-described among children with CKD-even prior to need for dialysis or transplantation; however, it is important to note that the preponderance of modern data on this topic do not support global delays but rather subtle, yet potentially pervasive challenges in neurocognition.The chronic kidney disease in children (CKiD) prospective cohort study has provided a wealth of data about the risk for neurocognitive deficit in parallel with CKD progression. 9,10Data from the CKiD study demonstrate an absence of significant global cognitive impairments among children with mild to moderate CKD (pre-transplantation); but, rather, average to slightly low-average intelligence quotient (IQ), as well as deficits in various executive functions, specifically attention regulation. 11,12Executive function is an umbrella term for a variety of related neurocognitive functions -including attention, working memory, inhibitory control, and cognitive flexibility-that are generally utilized in goal-directed behaviors.Executive functions depend on neural circuits including the frontal and temporal lobes (among others), which continue to develop until early adulthood. 13Reduced performance or even impairment in aspects of executive function, such as inhibitory control for example, may manifest itself as impulsive behaviors and difficulty concentrating in class instruction.
These cognitive challenges are known to affect current and future academic and employment success in pediatric patients with chronic disease, including CKD. 14,15 Among children with pre-dialytic/pre-transplant CKD, increased disease severity-as measured by estimated glomerular filtration rate (eGFR, mL/min/1.73[18]

| KIDNE Y TR ANS PL ANTATION AND NEUROCOG NITION
Cognitive deficits may emerge in parallel with CKD progression, severity, and duration; thus, it is conceivable that kidney transplantation might remediate neurocognitive deficits present in advanced CKD/ESKD.It is generally thought that cognition improves following kidney transplantation; however, our knowledge on this topic is limited by the sparsity of high-quality data in the setting of the relative rarity of pediatric patients with a KT.Existing work within this population is impacted by wide heterogeneity in age at transplant, variable dialysis exposure/duration, and unaccounted cofounders which persist following transplantation, including maintenance immunosuppressive regimens, and socio-economic status.Furthermore, there is a paucity of literature evaluating neurocognition pre-and post-transplantation with only three published, longitudinal studies to date (Table 1).

| General intelligence (IQ)
General intelligence (IQ) represents a global measure of multiple cognitive abilities or processes including but not limited to verbal comprehension, spatial reasoning, and working memory-all of which allow people to interact with and learn from their environment. 34As described within the previous section, children with CKD are at risk for cognitive deficits in the domain of general intelligence which may worsen as kidney disease progresses to the need of dialysis or transplant.It is currently unclear how kidney transplantation impacts the general intelligence of pediatric KT recipients as limited existing research has produced conflicting results.
A subset of cross-sectional and longitudinal studies suggests that kidney transplantation has a strong, positive impact on intelligence in pediatric patients.In comparison to pediatric dialysis patients, cross-sectional data support that KT recipients perform better on written language and mathematics Woodcock-Johnson achievement tests; however, there were no significant differences between the two groups in overall IQ. 20 Similarly, a longitudinal study by Icard et al. found a significant improvement in tests of general intelligence (i.e., Mullen Scales of Early Learning and Wechsler Abbreviated Scale Intelligence) among pediatric KT recipients in comparison to those with CKD who had not received a transplant. 25It is important to note, however, that while authors cited mean change in IQ of 12.7 points, children with CKD continued to test within the low-average range after transplantation. 25 contrast, other work indicates that impairments in general intelligence post-transplant may be highly variable, or even may not published a longitudinal study that followed the cognitive abilities of children with kidney failure alongside healthy controls.The authors report mixed results, in which performance in some domains appears to worsen (i.e., memory and learning ability), while other domains (i.e., visual perception, verbal ability, and motor skills) indicated improvement in KT patients. 19Cross-sectional data demonstrate persistence of low-average IQ scores 23,24 -or even worsened full-scale intelligence quotient (FSIQ) 22,26,30,32 -when comparing KT recipients with healthy controls.We recently showed evidence of reduced FSIQ in KT recipients relative to patients who had not yet received a transplant. 33These findings were further supported by longitudinal post-hoc analyses which indicated change in FSIQ and nonverbal scores decreased significantly from pre-to posttransplant in nine individuals. 33rthermore, disease-related factors may increase the risk for deficits in IQ post-transplant.[31] We recently reported that children transplanted at an older age (≥80 months) had significantly lower FSIQ, verbal IQ, nonverbal IQ, and memory scores. 33Medical comorbidities which are common prior to transplantation, such as anemia or dialysis modality and duration, as well as continued comorbidities associated with post-transplant care like maintenance immunosuppression may limit potential cognitive improvements following kidney transplantation.

| Executive function
In contrast, we recently showed processing speed-the ability to quickly integrate multiple types of information and utilize this input to perform a task-significantly decreased from pre-to post-transplant in eight KT patients. 33

| Summary
Taken together, published data lend an inconsistent description of the neurocognitive abilities of pediatric CKD patients after KT that is limited by relatively small sample sizes, as well as nominal contemporary data published on the topic of cognitive outcomes following KT to inform how pediatric patients fare in more modern cohorts.
However, despite an overall lack of clarity, several published studies report no significant change or even worsening of cognitive abilities of pediatric KT patients with risk for subtle yet present deficits in IQ, executive function (including memory and attention), and academic achievement.

| KIDNE Y TR ANS PL ANTATION AND B R AIN S TRUC TURE
Despite the recognition of neurocognitive deficits in the pediatric KT population, there is a critical gap in our understanding of the neurobiological mechanisms driving persistent neurocognitive deficits following pediatric KT.Neuroimaging offers tools to noninvasively and quantitatively evaluate both brain structure and brain function; however, there is a paucity of data on the topic of brain structure and function in pediatric KT recipients.
This gap may be attributable to some of the challenges associated with implementing neuroimaging research in pediatric samplesfor example, the financial cost to implement a research-based neuroimaging study is a notable barrier to large-scale neuroimaging research.Similarly, the need for young participants to remain stationary during neuroimaging assessment may pose a barrier to non-sedated, research-based scanning.

| Structural morphometry
The use of magnetic resonance imaging can provide both qualitative and quantitative opportunity to assess the brain.The majority of published pediatric KT neuroimaging studies are qualitative in nature, that is, extrapolated from review of clinical neuroimaging studies.Moreover, most studies are published prior to the year 2010. 41obally, this body of work suggests the potential for neurological changes (e.g., posterior reversible encephalopathy syndrome, brain infarcts, and ischemic lesions) to persist following KT. 42,43 contrast to qualitative neuroimaging research, quantitative neuroimaging provides discrete, measurable information related to morphometrical features of the brain, such as regional brain volume.Quantitative data from our own laboratory suggest that children with mild to moderate CKD-prior to need for dialysis and/or transplantation-exhibit significantly decreased cerebellar gray matter in comparison to healthy controls, 44 suggesting that changes in neurological architecture may be evident early in the disease course of CKD.Structural morphometry data in adults with mild to severe CKD (i.e., pre-transplantation) have similarly shown regional decrements in the hippocampus that were negatively associated with kidney function (i.e., eGFR) and cognitive performance. 45ere are only two cross-sectional studies of pediatric KT recipients which identify structural abnormalities using quantitative, research-based neuroimaging methods.Lijdsman et al., identified significantly smaller subcortical volume (i.e., nucleus accumbens) in a small sample of 10 pediatric KT recipients. 46However, this study included a wide range of patient ages spanning from childhood into adulthood; thus potentially limiting the ability to detect structural brain differences in juxtaposition to pediatric KT. 47 Similarly, Hartung et al., identified lower gray matter volumes in the whole brain and frontal and parietal regions, as well as increased whole brain white matter volume in pediatric KT recipients in unadjusted models. 48Notably, once adjusted for multiple comparisons, these differences in brain morphometry were no longer significant, and none of the previously identified regions were associated with neurocognitive outcomes.

| White matter integrity
White matter undergoes some of its most dynamic changes during childhood 49,50 ; thus, it is plausible that the presence of a chronic illness in childhood may negatively impact ongoing white matter maturation. 49,51,52[55] Diffusion tensor imaging (DTI) is a magnetic resonance imaging method that measures the movement of water molecules to characterize white matter within the brain. 52,56,57Scalar measurements, including mean diffusivity (MD) and fractional anisotropy (FA), are commonly used to quantify WMI at specified regions of interest and/or within smaller voxel-based areas down to 1 mm 3 voxels. 58MD is an average of diffusion properties that considers the axial and radial diffusion of water molecules, whereas FA measures the degree of directionality along a white matter tract.Lower FA and higher MD are associated with abnormal WMI on DTI. 59 children, it is currently unknown whether abnormalities in WMI are altered by kidney transplantation, and whether any potential improvements in WMI will translate to normalization of cognitive function.The only two cross-sectional studies that have investigated WMI post-transplant in children and young adults showed evidence for globally lower WMI. 46,60Although limited in nature, these data are consistent with published data from children with pre-transplant CKD that demonstrated globally lower WMI (as measured by decreased FA) and regionally lower WMI within the corpus callosum, cingulum, and internal capsule in a sample of children with pre-transplant CKD. 61e adult literature is similarly scarce on WMI associated with KT.3][64] This may be attributable to differences in age and duration of disease onset and the potential temporal impact of these disease-specific variables on brain growth and maturation. 65

| Summary
Our understanding of the impact of kidney transplantation on neurocognition is limited by the lack of longitudinal, quantitative neuroimaging studies evaluating the relationship between kidney transplantation and cognitive function in pediatric recipients.Although adult data support positive changes in brain structure and function post-transplant, it is unclear if pediatric patients experience the same improvements and-if so-whether these changes are sufficient to resolve cognitive deficits.

| IMPAC T OF LONG -TERM IMMUN OSU PPR E SS I ON ON THE B R AIN
Immunosuppression following KT is critical to prevent rejection and promote graft longevity.Immunosuppressive regimens for pediatric KT recipients typically include a combination of calcineurin inhibitors (CNIs), antiproliferative agents, mammalian target of rapamycin inhibitors, and/or corticosteroids. 66,67Children remain on a combination of such medications indefinitely as required for maintenance of their transplant graft.However, long-term exposure to immunosuppressive protocols may negatively impact the developing brain and neurocognitive function of pediatric KT recipients.

| Calcineurin inhibitors (CNIs)
Two of the most used CNIs in post-transplant care are tacrolimus and cyclosporine A. Calcineurin (CaN) is a calcium/calmodulindependent serine/threonine phosphatase that activates calciumdependent signal transduction pathways throughout the body. 68As a result, CaN has many critical functions in several body systems, including in the immune system, kidney and central nervous system (CNS). 68In the immune system, CaN is critical for T-cell activation. 69lcineurin inhibition prevents T-cell activation by inhibiting the phosphatase activity of CaN within the leukocyte, thereby preventing the transcription of interleukin-2 and translocation of nuclear factor of activated T cell. 70[73][74][75] Tacrolimus-associated neurotoxicity has been well-documented in both in vivo and in vitro models.For this review, we will focus on animal models.Administration of tacrolimus was found to reduce oxygen consumption and adenosine triphosphate synthesis within rat forebrain mitochondria. 76Similarly, neurological symptoms (i.e., seizures or tremors) increased as the intracerebral concentration of tacrolimus was raised over pharmacological threshold in rats. 77,78In comparison to healthy animals, rats administered tacrolimus had a significant decrease of brain-derived neurotrophic factor (BDNF) in the dentate gyrus and CA3 region of the hippocampus. 79Since BDNF is critical for the development and survival of neurons, as well as neuroplasticity, 80,81 reduction in BDNF levels can disrupt these critical processes with potential for cognitive dysfunction.Animal behavioral data support this hypothesis: rodents given tacrolimus demonstrate perturbations in memory and spatial learning associated with decreased excitatory synaptic potentials in the hippocampus. 82mited investigation in adult KT population suggests CNI use has a negative impact on cognitive function.Martinez-Sanchis et al.
found attention and working memory deficits in patients treated with tacrolimus. 83Similarly, in comparison to healthy controls, adult kidney and liver transplant recipients maintained on tacrolimus showed significantly worse cognitive function post-transplant, especially within the domain of visuospatial abilities. 84This suggests that the effect of CNIs may partially explain the risk for persistent neurocognitive deficits among adult KT recipients.The effect of chronic tacrolimus use on cognition has not been directly assessed in pediatric KT recipients.

| Corticosteroids
Corticosteroids (e.g., prednisone and methylprednisolone) are utilized for both induction and maintenance immunosuppressive regimens.Corticosteroids suppress the immune system by binding to the glucocorticoid receptor which translocates to the nucleus and promotes gene transcription of anti-inflammatory proteins. 85[88][89] Cognitive impairments are also observed with prolonged corticosteroid use.Deficits have been observed in memory and recall, attention, mental processing speed, general intelligence, and executive function. 90,91e exact mechanism underlying neurotoxicity of corticosteroids is not yet understood; however, current evidence suggests corticosteroid-induced insults to the hippocampus may underlie cognitive deficits.Corticosteroids are known to alter critical aspects of synaptic transmission within the hippocampus, including metabolite transport in neurons and astrocytes, glutamatergic (i.e., excitatory) signaling, and calcium channel conductance. 92,93These cellular changes can hinder synaptic potentiation within the hippocampus and may manifest as serious impairments to learning and memory. 92,93Chronic corticosteroid use is also associated with neuronal damage, dendritic atrophy, and decreased neurogenesis in the hippocampus. 94,95Expression of BDNF is reduced in response to chronic corticosteroid exposure, which may negatively influence several cellular processes critical for cognition, including neuroplasticity and cellular excitability. 94e developing brain may be particularly vulnerable to the neurotoxic side effects of corticosteroids, making the need for long-term immunosuppression in pediatric patients particularly worrisome.In fetal primates, administration of corticosteroid betamethasone changed cytoskeletal and synaptic proteins critical for neurogenesis and plasticity. 96In humans, there is evidence from cancer literature that suggests dexamethasone or prednisone exposure at a young age negatively impacts neurocognition, specifically memory and verbal abilities. 97However, the long-term impact of chronic or prolonged corticosteroid use on the neurocognitive development has yet to be systematically evaluated in pediatric KT recipients.

| Antimetabolites
Azathioprine and mycophenolate mofetil are commonly used antimetabolite medications used in the KT population.Antimetabolites inhibit the immune system by inhibiting de novo and salvage pathways of nucleic acid synthesis. 98As a result, antimetabolites are extremely useful drugs to prevent proliferation of immune cells.
There is little to no evidence of neurotoxicity or insults to cognitive function with prolonged exposure to azathioprine and mycophenolate.In fact, animal data suggest mycophenolate mofetil may confer a neuroprotective effect. 99Furthermore, in humans, it is difficult to isolate and describe the relationship between prolonged use of antimetabolites and cognitive function for KT recipients given the reliance on multi-drug immunosuppression-including CNIs and corticosteroids with known neurotoxic effects.

| Summary
Medical immunosuppression is the mainstay of preventing allograft rejection; however, the impact of chronic exposures to immunosuppression medicine on neurodevelopment in pediatric CKD patients is poorly understood.CNS-specific symptoms associated with longterm immunosuppression are variable.It is important to acknowledge that seemingly minor relevant symptoms, such as headaches and tremor, may confer a barrier to learning in the classroom and with future employment.Further research is necessary to ensure that pediatric transplant providers can make informed decisions about immunosuppressive therapy in young patients.

| THE CON UNDRUM WITH COG NITI ON AND TR ANS ITION TO ADULTHOOD
The pediatric KT population is at highest risk for allograft (transplant) loss due to rejection between 18 and 25 years of age. 100 Furthermore, this peak in allograft loss coincides with transition of care from pediatric to adult providers and increased patient autonomy in healthcare decision-making.A host of cognitive abilities-including executive function (planning, organization), attention, and memoryare required to successfully follow complex post-transplant care regimens and maintain allograft health.Although outside the scope of this review, it is important to also recognize that the ability to adhere with complex medical care plans may be further impacted by the individual's emotional development, ability to perform activities of daily living, and financial independence-all which may be impacted by neurocognitive deficits.
One commonly cited barrier to medication adherence is remembering to take prescribed medications. 101Focal attention and memory deficits may be compounded by poor organizational skills (e.g., planning)-creating a perfect storm that perpetuates "forgetting." 102,103Furthermore, post-transplantation maintenance regimens are incredibly complex and subject to frequent changes, which could be troublesome for young patients beginning to assume more autonomy and responsibility for their health.Adolescent and young adult KT recipients with impairments in executive function are also more likely to report increased medication nonadherence. 104These results emphasize the importance of how deficits in planning, initiating, and goal-directed behavior may negatively impact health outcomes in the pediatric and young adult KT population-as well as the cognitive factors that care teams and/or caregivers should consider during the pediatric-to-adult transition.

| CON CLUS ION
The long-term impact of pediatric kidney transplantation on cognition remains unclear; however, the body of available evidence suggests that kidney transplantation may not fully resolve neurocognitive issues.Neurocognitive assessment is a critical, yet likely under-utilized, component of care for this patient population and should be performed in conjunction with a licensed (neuro)psychologist.Awareness of neurocognitive deficits may allow the pediatric nephrologist (as well as families, educators, and general pediatricians) to better educate and inform the pediatric KT recipient of the need for optimal medication adherence in a way the leverages the individual's cognitive skills and minimizes cognitive reliance on areas of weakness.

TA B L E 1
Summary of the literature on pediatric kidney transplant and neurocognitive outcomes.

N Treatment group Type of study Age at assessment of pediatric transplant patients: years ± SD and (range) Findings
In comparison to population norms, pediatric transplant patients have poorer neurodevelopmental outcomes Note: Ranges were recorded when standard deviation for age at assessment was not available.Longitudinal studies are highlighted in bold font.Adapted from Lullmann et al. 33 Abbreviations: CAT, cognitive abilities test; CPT, connors continuous performance test; ESKD, end-stage kidney disease; FSIQ, full-scale intelligence quotient; IQ, intelligence quotient; PASAT/CHIPASAT, Paced Auditory Serial Addition Test or Children's Paced Auditory Serial Addition Test. a Indicates median age at assessment.fully resolve following kidney transplantation.In 1990, Fennell et al.
37,26nths of age or greater relative to those transplanted at a younger age. 33larly, cross-sectional data indicate that executive dysfunction may continue after KT.Haavisto et al. and Falger et al. found impaired working memory performance in pediatric KT recipients.24,26PediatricKTrecipientswithout neurological comorbidities were also found to have impairments on tests Even prior to need for dialysis or transplant, children with CKD are at risk for academic underachievement.37Thispattern of limited academic success can follow children into adulthood, even after trans- 39,40tial persistent deficits in processing speed may be exacerbated by older age at transplant, as suggested by significantly lower processing speed scores in children transplanted at plantation.Low academic achievement in grade school can create a notable barrier to college entrance, successful degree completion, and future job attainment.In one sample, out of 12 young adult KT recipients, nine did not complete a college degree38; furthermore, only a quarter of patients were employed full-time.Compared to the healthy population, both dialysis and transplanted patients may be less likely to endorse employment or obtain average-to aboveaverage household income.39,40