*5.1. Dietary Clues*

There is some evidence that dietary lipids and sodium may behave as chronodisruptors and, more specifically, that salt may be a chronodisruptor in CKD. Indeed, salt loading aggravates the inverse relationship between melatonin secretion, assessed as urinary levels of its metabolite 6-sulfatoxymelatonin (aMT6s) and albuminuria in CKD patients [54]. High salt feeding led to region-specific alterations in circadian clock components within the kidney and caused a 5.5-h phase delay in the peak expression of *Bmal1* and suppressed *Cry1* and *Per2* expression in the renal inner medulla, but not the renal cortex, of control rats. The phase delay in *Bmal1* expression appears to be mediated by endothelin-1 because this phenomenon was not observed in endothelin receptor B (ETB)-deficient rats. Thus, high salt feeding leads to intrarenal circadian dyssynchrony in part through activation of ETB receptors within the renal inner medulla [55]. There is less information on the molecular mechanisms engaged by dietary lipids to influence circadian kidney rhythms. One possibility is through epigenetic regulation of gene expression. Thus, dietary lipids modulate the expression of miR-107, a miRNA that regulates the circadian system [56].

An area of research is focused on altering circadian rhythms by time-related dietary approaches (chrononutrition) or pharmacological substances (chronobiotics) [57]. In a randomized clinical trial, short chronotype-adjusted diet was more e ffective than the traditional hypocaloric diet in decreasing BMI, and waist circumference [58]. In a further trial, eating late was associated with decreased resting-energy expenditure, decreased fasting carbohydrate oxidation, decreased glucose tolerance and blunted daily profile in free cortisol concentrations [59]. In this regard, it is widely recognized that chronodisruption and mistimed eating have deleterious e ffects on metabolic health that may exceed those of eating an unbalanced diet, during the normal active phase [60]. How CKD may a ffect these relationships and to what extent chronotype-adjusted diets may provide any advantages to CKD patients is, at this point, unclear.

Diet may also influence the gu<sup>t</sup> microbiota. Gut bacteria modulate host rhythms via microbial metabolites such as butyrate and others, and amines and disturbed microbiome rhythms have been proposed to at least partially contribute to an increased risk of obesity and metabolic syndrome associated with chronodisruption [61]. Although there is little information on microbiota and chronodisruption in CKD, both obesity and metabolic syndrome increase the risk of CKD. Conversely, CKD has been associated with altered microbiota patterns and metabolites accumulated in CKD may modulate the gu<sup>t</sup> microbiota and butyrate production [62–64].
