**3. Concept of Chronodisruption**

The concept of chronodisruption was coined in 2003 by Thomas C. Erren, Russel J. Reiter and Claus Piekarski from the University of Cologne [24] (Figure 2). The term was meant to go beyond the concept of chronodisturbance, a general term they proposed to refer to modulations of rhythms over time that are not necessarily deleterious since physiological compensations may prevent the development of chronic disease resulting from altered rhythms. Chronodisturbance itself was a conceptual leap from more common concepts such as "circadian disruption" or "disruption of circadian rhythms" that sugges<sup>t</sup> that rhythms over 24 h can become desynchronized and that this may have adverse health effects, since these common terms may be more limited in time scope than chronodisturbance which may have a decade scope. Thus, circadian disruption may be caused by travel across several time zones, however, within a limited period of time within this new time zone, adaptation of the circadian rhythms to the new time zone occurs and there are no long-term consequences. By contrast, chronic work in night shifts will lead to chronodisturbance, that is to persistent desynchronization between time and activity. In 2009, they further elaborated on the chronodisruption concept, stating that "chronodisruption can be understood as a critical loss of time order, i.e., a disorder or chaos of an otherwise physiological timing at different organizational levels, including the gene expression levels in individual cells" and thus, it is "a breakdown of phasing internal biological systems appropriately relative to the external, i.e., environmental changes, which leads to chronobiological disorders" [25]. Following with the chronic night shift example, this would be considered chronodisturbance as long as there are no adverse consequences for health, and chronodisruption if this leads to adverse consequences for health. Furthermore, they characterized chronodisruptors as "exogenous and endogenous exposures or effectors which are chronobiologically active and can thus disrupt the timing and order, i.e., the temporal organization of physiologic functions and hierarchies" [25]. A clear example of a chronodisruptor is the use of artificial light or backlit screens during the night. They

additionally proposed that assessment of melatonin levels in saliva, urine and blood may be a robust biomarker of chronodisruption. While in some fields the concept was immediately grasped (In 2007, the International Agency for Research on Cancer classified shift-work that involves circadian disruption as probably carcinogenic to humans), it was not until 2013 that the term chronodisruption was used in the context of CKD [26] and only in 2019 was a second manuscript published on the topic [27].

**Figure 2.** Concepts of circadian disruption, chronodisturbance and chronodisruption. As compared to a normal circadian rhythm, circadian disruptions are characterized by altered circadian rhythm that may be short or long lived. Chronodisturbance is a chronic disruption of circadian rhythms that somehow leads to adaptive phenomena that limit its negative impact. Chronodisruption is a chronic disruption of circadian rhythms that results in disease. Chronodisruptors (not shown) are the factors driving chronodisruption. The normal circadian rhythm is shown as a green line in the left panel and as a discontinuous line in the other panels. A red line represents the altered circadian rhythm in the three left panels. Please note the different timelines shown in the horizontal axis, with chronodisturbance and chronodisruption implying chronicity.

While this is surprising given the chronic nature of CKD, its similarities with aging and the widely known fact that circadian rhythms may be disturbed in CKD, it does not mean that the nephrological community is not aware of disruption of circadian rhythms in CKD. Indeed, very active research is going on as attested by recent reviews [14,15,26,28,29]. However, CKD researchers may benefit from a wider use of the terms and concepts of chronodisruption and chronodisruptor. Thus, the mere concept of chronodisruptor may facilitate the search of chronodisruptors involved in CKD manifestations. These may potentially be abnormal levels of uremic toxins or abnormally low levels of uremia-related factors, among others.
