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Associations between neurofilament light-chain protein, brain structure, and chronic kidney disease

Abstract

Background

Neurofilament light-chain (NfL) protein is a blood-based marker of neuroaxonal injury. We sought to (1) compare plasma NfL levels in children with chronic kidney disease (CKD) and healthy peers, (2) characterize the relationship between NfL level and kidney function, and (3) evaluate NfL as a predictor of abnormal brain structure in CKD.

Methods

Sixteen children with CKD due to congenital kidney anomalies and 23 typically developing peers were included. Plasma NfL was quantified using single-molecule array immunoassay. Participants underwent structural magnetic resonance imaging. Multiple linear regression models were used to evaluate the association between plasma NfL levels, kidney function, and brain structure.

Results

An age × group interaction was identified whereby NfL levels increased with age in the CKD group only (estimate = 0.65; confidence interval (CI) = 0.08–1.22; p = 0.026). Decreased kidney function was associated with higher NfL levels (estimate = −0.10; CI = −0.16 to −0.04; p = 0.003). Lower cerebellar gray matter volume predicted increased plasma NfL levels (estimate = −0.00024; CI = −0.00039 to 0.00009; p = 0.004) within the CKD group.

Conclusions

Children with CKD show accelerated age-related increases in NfL levels. NfL level is associated with lower kidney function and abnormal brain structure in CKD.

Impact

  • NfL is a component of the neuronal cytoskeleton providing structural axonal support. Elevated NfL has been described in relation to gray and white matter brain volume loss. We have previously described the abnormal cerebellar gray matter in CKD.

  • We explored the relationship between NfL, CKD, and brain volume.

  • There is an accelerated, age-related increase in NfL level in CKD. Within the CKD sample, NfL level is associated with abnormal kidney function and brain structure. Decreased kidney function may be linked to abnormal neuronal integrity in pediatric CKD.

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Fig. 1: Age-related changes in neurofilament light-chain (NfL) protein levels in chronic kidney disease (CKD) and control groups.
Fig. 2: Association between neurofilament light-chain (NfL) protein levels and disease burden (a) and cerebellar gray matter volume (b).

Data availability

Anonymized data are not available in a public repository; however, it will be shared upon request from any qualified investigator.

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Acknowledgements

This study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (K23DK110443—L.A.H.).

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Contributions

Research idea and study design: E.v.d.P., L.A.H., and P.C.N.; data acquisition: L.A.H. and O.L.; data analysis/interpretation: L.A.H., O.L., E.v.d.P., J.S., and P.C.N.; supervision or mentorship: L.A.H., P.C.N., E.v.d.P., and O.L. Primary responsibility to drafting the paper: E.v.d.P., O.L., L.A.H., and J.S. All authors contributed important intellectual content during iterative manuscript drafts or revisions, accept personal accountability for the author’s own contributions, reviewed the document submitted for review, and agree to ensure that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Lyndsay A. Harshman.

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van der Plas, E., Lullmann, O., Hopkins, L. et al. Associations between neurofilament light-chain protein, brain structure, and chronic kidney disease. Pediatr Res (2021). https://doi.org/10.1038/s41390-021-01649-6

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