Early kidney transplantation improves neurocognitive outcome in patients with severe congenital chronic kidney disease

Hartmann, Hans; Hawellek, N; Wedekin, Mirja; Vogel, Charlotte; Das, Anibh M.; Balonwu, Katharina; Ehrich, J. H. H.; Haffner, Dieter; Pape, Lars

doi:10.1111/tri.12510

Cited by 26 publications

(19 citation statements)

References 27 publications

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“…reported neurocognitive outcomes in 12 patients with ESRD in first 16 months of life and noted that the intellectual and metacognitive functioning was lower than their sibling controls and earlier txp was associated with higher scores on their cognitive testing. Hartman et al . noted that early txp resulted in superior neurocognitive outcomes.…”

Section: Discussionmentioning

confidence: 99%

Anuria since birth: does it impact outcome of kidney transplant in infants?

Vyas¹,

Roberti²

2016

Pediatric Transplantation

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Kidney transplantation (txp) in infants has recently made much progress but provides a unique challenge in infants anuric since birth. Little data exists on outcome of renal txp recipients with anuria since birth. Retrospective chart review was done for outcome of 27 children with wt ≤15 kg and they were divided into two groups: Group A (N=21) with urine output and Group B (N=6) anuric since birth had their urological complications and long-term outcome compared. Median age at the time of txp 18 vs 23 months, mean wt 10.8 vs 11.8 kg, and mean ht 77 cm in both, mean follow-up post-txp: 9.4 vs 5.6 years, and neurological problems were noted in 48% and 33% in Group A and Group B. There was no graft thrombosis or post-transplant lymphoproliferative disease and only two rejections. Anuric Group B were older, had more post-txp urological surgeries (66% vs 19%) and UTIs (66% vs 38%) compared to Group A. The overall graft survival at 1, 5, and 10 years was 96%, 86%, and 70%; patient survival at 1, 5, and 10 years was 96%, 85%, and 85%. Long-term graft outcomes in small children, anuric prior to txp, were excellent despite higher rates for UTIs and urological complications.

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Section: Discussionmentioning

confidence: 99%

Anuria since birth: does it impact outcome of kidney transplant in infants?

Vyas¹,

Roberti²

2016

Pediatric Transplantation

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“…uremia [30]. Indeed, memory deficit is common in children and adults suffering from chronic kidney disease (CKD) and has been associated with elevated FGF23 serum in these patients [30][31][32]. Transgenic mice overexpressing FGF23 display cognitive dysfunction, an impaired spatial learning, and memory deficit [33].…”

Section: Introductionmentioning

confidence: 99%

Klotho and fibroblast growth factor 23 in cerebrospinal fluid in children

et al. 2016

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The fibroblast growth factor (FGF) 23/Klotho axis is a principal regulator of phosphate hemostasis and vitamin D metabolism, but limited data is available on its role in the central nervous system. Here, we investigate soluble α-Klotho (sKlotho) and C-terminal as well as intact FGF23 in cerebrospinal fluid (CSF) and plasma and their relationship to mineral metabolism parameters in humans. In 39 children aged 0.3-16.8 years undergoing lumbar puncture for the exclusion of inflammatory neurological disease, sKlotho and FGF23 were investigated by Western blot analysis, followed by ELISA quantification in CSF and plasma. The percentage of intrathecal synthesis of both proteins was calculated by measuring both the expected and observed CSF/plasma ratios of sKlotho and FGF23. The secreted (KL1) and cleaved (KL1+KL2) isoforms of sKlotho, and FGF23 were clearly detected in CSF in all subjects, although protein levels were lower compared to those of plasma samples (each p < 0.01). The intrathecal percentage of CSF sKlotho and FGF23 synthesis amounted to 98 and 99 %, respectively. CSF sKlotho levels were higher in boys than in girls (p < 0.01), and correlated positively with plasma C-terminal FGF23 concentrations (p < 0.05) and standardized height (p < 0.01). Importantly, there were no significant correlations between plasma and CSF levels of sKlotho or FGF23. Plasma sKlotho as well as C-terminal and intact FGF23, respectively, were associated with parameters of mineral metabolism These results provide evidence that cleaved and secreted sKlotho and FGF23 are present in CSF, mainly derived from brain and affected by sex, height, and mineral metabolism parameters in children. Nevertheless, the absence of significant associations between plasma and CSF levels of Klotho and FGF23, respectively, suggest that the regulation of Klotho and FGF23 may be different between organs secreting these hormones into blood and CSF.

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“…; Hartmann et al . ). Congenital CKD, and severity and duration of CKD have been identified as risk factors for memory deficits in children (Slickers et al .…”

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confidence: 97%

Fibroblast growth factor 23 signaling in hippocampal cells: impact on neuronal morphology and synaptic density

Hensel

Schön

Konen

et al. 2016

Journal of Neurochemistry

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Endocrine fibroblast growth factor 23 (FGF23) is predominantly secreted by osteocytes and facilitates renal phosphate excretion. However, FGF23 is also present in cerebrospinal fluid. In chronic kidney disease, FGF23 serum levels are excessively elevated and associated with learning and memory deficits. Structural plasticity of the hippocampus such as formation of new synapses or an altered dendritic arborization comprises a cellular and morphological correlate of memory formation. Therefore, we hypothesize that FGF23 alters hippocampal neuron morphology and synapses. To address this, we prepared primary murine hippocampal cultures and incubated them with recombinant FGF23 alone or together with a soluble isoform of its co-receptor a-Klotho. Neuronal expression of a fluorescent reporter allowed for a detailed evaluation of the neuronal morphology by Sholl analysis. Additionally, we evaluated synaptic density, identified by stainings, for synaptic markers. We show an enhanced number of primary neurites combined with a reduced arborization, resulting in a less complex morphology of neurons treated with FGF23. Moreover, FGF23 enhances the synaptic density in a FGF-receptor (FGF-R) dependent manner. Finally, we addressed the corresponding signaling events downstream of FGF-R employing a combination of western blots and quantitative immunofluorescence. Interestingly, FGF23 induces phospholipase Cc activity in primary hippocampal neurons. Co-application of soluble a-Klotho leads to activation of the Akt-pathway and modifies FGF23-impact on neuronal morphology and synaptic density. Compared with other FGFs, this alternative signaling pattern is a possible reason for differential effects of FGF23 on hippocampal neurons and may thereby contribute to learning and memory deficits in chronic kidney disease patients.

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Early kidney transplantation improves neurocognitive outcome in patients with severe congenital chronic kidney disease

Cited by 26 publications

References 27 publications

Anuria since birth: does it impact outcome of kidney transplant in infants?

Anuria since birth: does it impact outcome of kidney transplant in infants?

Klotho and fibroblast growth factor 23 in cerebrospinal fluid in children

Fibroblast growth factor 23 signaling in hippocampal cells: impact on neuronal morphology and synaptic density

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