Sleep-Promoting Material Extracted from Peritoneal Dialysate of Patients with End-Stage Renal Disease and Insomnia
Authors: Moldofsky Harvey , Martin James , James Krueger , Walter Charles , Dinarello A. , Lue Franklin A. , Quance Grace , Oreopoulos Dimitrios G. 
Published: February 2020

We studied four patients with end stage renal disease treated by continuous ambulatory peritoneal dialysis (CAPD) who complained of chronic insomnia and fatigue. Overnight polysomnography showed a disorder of sleep maintenance that was associated with nocturnal myoclonus. Sleeppromoting substance(s), Factor S-like material, that was extracted from the patient's dialysate effluent, was somnogenic and pyrogenic in a rabbit bioassay. Another proposed sleep substance, lnterleukin -I, isolated by gel filtration, also was present in the dialysate effluents of all patients. Altered metabolism and/or loss of these substances from the effluent may contribute to the chronic insomnia and fatigue of CAPD patients.

End-stage renal disease (ESRD) patients are restored to medical “health” by dialysis, but commonly they complain of depression, fatigue, and insomnia. Profound sleep disturbances have been described (1–4) and are associated with nocturnal myoclonus (5). These sleep-related, periodic, involuntary leg movements occur at intervals of 20 to 40 sec and disrupt the continuity of sleep (6). In their review of sleep-wakefulness disorders associated with nocturnal myoclonus Coleman et al (7), suggest that a chronic sleep-wake disturbance may lead to these periodic movements during sleep rather than the converse. However, the physiologic mechanism for the involuntary leg movements during sleep remains unknown.

Endogenous substances that promote sleep -neuromodulators, hypnotoxins have been investigated for many years (8). One of these, Factor S, has been extracted from human urine (9) and rabbit brain (10). Factor S derived from urine has been identified as a muramyl tetrapeptide with a molecular size of 922 daltons (11). Picomole quantities of this substance administered intracerebroventricularly were sufficient to induce excess slow-wave sleep (SWS) in rabbits for 6 or more hours (11). Some chemical analogues to Factor S, such as NAc-Mur-L-ala-D-isogln -a synthetic adjuvant called muramyl dipeptide or MDP, also were found to be somnogenic (12, 13). MDP and other related muramyl peptides also are pyrogenic and immunostimulatory (14). These responses could be elicited either directly by these synthetic compounds or through the leukocytic monokine interleukin-l (IL-l) (15), whose synthesis and release can be stimulated by muramyl peptides (16). IL-l, a polypeptide of about 15,000 daltons (17, 18), has the capacity to promote SWS (19). Recently IL-l has been demonstrated in astrocytes exposed to endotoxin (20). Thus astrocyte-derived IL-l may mediate certain brain functions, such as sleep.

This paper will show that the sleep physiology of patients undergoing continuous ambulatory peritoneal dialysis (CAPD) is severely disrupted with noctumal myoclonus, i.e., sleep-related, involuntary, periodic leg movements. Further, dialysis fluids obtained from these patients contain a Factor S-like material and IL-l. It is possible that, in ESRD patients, altered metabolism and/or loss of the above-mentioned sleep-promoting substances may contribute to chronic insomnia and daytime fatigue.