**6. The Way Forward**

Table 3 summarizes some key answered questions regarding chronodisruption, chronodisruptors and CKD. A key to the clinical translation of the current state of knowledge regarding chronodisruption in CKD, beyond preventing and treating CKD itself, is to identify targetable chronodisruptors.


**Table 3.** Some key answered questions regarding chronodisruption, chronodisruptors and CKD.

An issue frequently overlooked by researchers is that the most common laboratory animals used to study kidney disease are rats and mice, which are nocturnal animals. Thus, essentially all experiments are performed during their inactive period and manipulation during this period risks creating chronodisruption which may have an unknown impact on experimental results [20]. This emphasizes the need for human studies. However, clinical research into CKD-related chronodisruption would require easy access to non-invasive techniques that allow monitoring of biological rhythms beyond blood pressure. Wrist skin temperature has been proposed as a new index for evaluating circadian system status [97]. Development of chronodisruption scores [98] and computational model of the renal circadian clock [99] would also facilitate clinical research. Longitudinal studies and ideally, interventional trials, would provide information on the causality and direction in the clinical association of disturbed sleep (a likely manifestation of chronodisruption) and CKD. In this regard, in a prospective cohort study of over 4000 participants from the Nurses' Health Study, shorter sleep duration was prospectively and independently associated with faster decline in renal function [100].

Chronopharmacology studies how biological rhythms influence pharmacokinetics, pharmacodynamics, and toxicity, and determines whether time-of-day administration modifies the pharmacological characteristics of the drug. Chronotherapy applies chronopharmacological studies to clinical treatments, determining the best biological time for dosing [101]. Well known examples in CKD patients include phosphate binders. In addition, there is a school of thought supported by meta-analyses results and clinical trials emphasizing the benefits of nighttime administration of anti-hypertensive medication [14].

In a recent clinical trial in hypertensive patients without CKD, ingestion of at least one blood pressure-lowering medication at bedtime resulted in improved ambulatory blood pressure control with a significant further decrease of asleep blood pressure and reduced risk of incident CKD than early morning administration [102].

While this may be initially viewed as CKD prevention, it is likely that it may additionally represent slowing of CKD progression, Thus, current diagnostic criteria for CKD are late events and patients who

progressed to meet the diagnostic criteria for CKD during the trial likely had baseline subclinical CKD, maybe as cause of hypertension [103]. New upcoming drugs may also benefit from chronopharmacology studies. Thus, HIF activators were recently approved for clinical use in China and are expected to be soon available worldwide to treat uremic anemia [104]. Whether chronopharmacology may optimize timing of administration is currently unknown. Finally, cardiovascular and nephroprotective e ffects have been described for melatonin [105].

**Author Contributions:** All authors have contributed and read and agreed to the published version of the manuscript.

**Funding:** This work was funded by FIS CP14/00133, PI16/02057, PI18/01366, PI19/00588, PI19/00815, DTS18/00032, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071, National Institute of Health (2R01AI063331), ISCIII-RETIC REDinREN RD016/0009 Fondos FEDER, FRIAT, Sociedad Española de Nefrología, Comunidad de Madrid B2017/BMD-3686 CIFRA2-CM, Miguel Servet MS14/00133 to MDSN and ABS. IIS-Fundacion Jimenez Diaz Biobank, part of the Spanish Biobanks Platform (PT17/0015/0006). The APC was funded by PI19/00815.

**Conflicts of Interest:** The authors declare no conflict of interest.
