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Volume 15 No. 11
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Commentary
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Seeking the Cause of Restless Legs Syndrome in Chronic Kidney Disease

Anne Marie Morse, DO1; Sanjeev V. Kothare, MD2
1Department of Child Neurology and Sleep Medicine, Janet Weis Children’s Hospital, Geisinger, Danville, Pennsylvania; 2Department of Child Neurology and Sleep Medicine Cohen Children’s Medical Center, Northwell Health, Lake Success, New York

ABSTRACT

Morse AM, Kothare SV. Seeking the cause of restless legs syndrome in chronic kidney disease. J Clin Sleep Med. 2019;15(11):1559–1560.


Restless legs syndrome (RLS) is a neurologic condition that is clinically diagnosed based on its unique presentation. The hallmark features include an urge to move the legs, often due to unpleasant sensations. Activity may provide transient relief while rest often exacerbates the condition. Symptoms demonstrate a nocturnal predominance, and these features are not better explained by any another condition.1 While there is no diagnostic test available to confirm RLS, polysomnography if performed, may show increased periodic limb movements (PLMs).2 RLS may be idiopathic or secondary to other comorbid conditions. It is common in idiopathic RLS to have a positive family history, as there appears to be a strong genetic component.3 Frequently, patients with RLS have low serum iron or low serum ferritin levels, with serum ferritin inversely correlating with severity of RLS symptoms. Iron is an essential cofactor for tyrosine hydroxylase, which is involved with dopamine metabolism in the brain and suggestive to be highly relevant to this sleep-related movement disorder.4 It has been postulated that RLS secondary to comorbid disease may have alternative factors contributing to the development of symptoms. For example, in chronic kidney disease (CKD), suggested associated factors include the intake of calcium antagonists, decreased baseline intact parathyroid hormone, frequent blood draws, lower serum transferrin saturation, and the duration and type of dialysis.5

In this issue of the Journal of Clinical Sleep Medicine, Riar et al look at evaluating the role of inflammation versus iron deficiency in the development of RLS symptoms with a cross-sectional analysis of 3 groups of children: CKD without dialysis, CKD with dialysis, and CKD after renal transplant.6 Iron status was measured by serum ferritin, transferrin saturation, hemoglobin, and mean corpuscular volume. Inflammation was measured by high sensitivity C-reactive protein. The design of the study was developed with an intention to compare RLS prevalence between children with CKD and age matched healthy controls. They found no identified difference in RLS prevalence across groups. Neither iron deficiency nor inflammation were identified as significant contributors to development of RLS symptoms. A nonsignificant trend to increased inflammation was seen in patients with RLS. They hypothesize that this may be related to inadequate power.

That inflammation may be causative for RLS may seem counterintuitive to some readers, at first glance; as a deficiency (< 50 ng/mL in children and < 75 ng/mL in adults) of ferritin, a storage protein for intracellular iron, may also be an acute phase reactant or biomarker of inflammation. There may be ambivalence in the role of ferritin, particularly in children with CKD, as this may be less useful than an alternative measure of iron status, namely hepcidin. Hepcidin is a hormone primarily secreted by hepatocytes that regulates iron levels by binding to ferroportin and is closely associated with both iron overload and deficiency.7 Hepcidin level and hepcidin/ferritin ratio have been identified as being positively correlated with PLMs during sleep and wakefulness, which is not the case for ferritin alone.7

It is also important to recognize that the peripheral nature of the environment being sampled may not, and likely does not, represent the biologic substrates available centrally. RLS is a neurologic disease believed to be related to the dysfunction of dopaminergic communication of the nigro-striatal system, where iron is an important cofactor. In fact, low brain iron concentrations have been found to be related to dysfunction of iron transportation from serum to the central nervous system.8 This is vitally important when considering children with CKD, where the peripheral status is heavily influenced by either impaired clearance mechanisms or artificial clearance via dialysis. This may influence the penetration of iron through the blood brain barrier and consequent central nervous system iron status. Without simultaneous cerebrospinal fluid or brain sampling of iron status, one should therefore question whether the evaluation of blood and plasma accurately represents iron status centrally and can reliably distinguish the role of iron versus inflammation as a contributory factor. In addition, why renal transplant failed to correct symptoms of RLS in their patients is also not clear.

The evaluation and identification of unique risk factors and modifiable biomarkers in children with RLS related to CKD may lead to a more optimal approach for prevention and treatment strategies of RLS in these pediatric patients. This has the potential to lead to a better quality of life, reduced need for sedative/hypnotics and improved sleep. The authors appropriately note the possibility that the study is underpowered, and from a single center, to detect differences in RLS in CKD versus RLS in healthy controls. This pilot data should provide impetus to a larger scale multicenter study to further explore these relationships. Future studies should also obtain additional evaluations including hepcidin and cerebrospinal fluid sampling/specialized brain imaging techniques to assess iron content to provide a better understanding of the pathophysiology in this population.

DISCLOSURE STATEMENT

All authors have seen and approved the manuscript. Dr. Sanjeev Kothare reports no conflicts of interest. Dr. Anne Marie Morse has served on advisory boards and as a consultant for Jazz Pharmaceuticals and is on the speaker’s bureau for Jazz Pharmaceuticals. She is an investigator for Jazz Pharmaceuticals, Balance Therapeutics and Avadel Pharmaceuticals. She receives grant funding from NIH/NIMH. These disclosures are unrelated to the present commentary.

REFERENCES

1 

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2 

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Winkelmann J, Schormair B, Xiong L, Dion PA, Rye DB, Rouleau GA. Genetics of restless legs syndrome. Sleep Med. 2017;31:18–22. [PubMed]

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6 

Riar SK, Greenbaum LA, Bliwise DL, Leu RA. Restless legs syndrome in chronic kidney disease: is iron or inflammation status to blame? J Clin Sleep Med. 2019;15(11):1629–1634

7 

Dauvilliers Y, Chenini S, Vialaret J, et al. Association between serum hepcidin level and restless legs syndrome. Mov Disord. 2018;33(4):618–627. [PubMed]

8 

Mizuno S, Mihara T, Miyaoka T, Inagaki T, Horiguchi J. CSF iron, ferritin and transferrin levels in restless legs syndrome. J Sleep Res. 2005;14(1):43–47. [PubMed]