Abstract
Multiple physiological variables change over time in a predictable and repetitive manner, guided by molecular clocks that respond to external and internal clues and are coordinated by a central clock. The kidney is the site of one of the most active peripheral clocks. Biological rhythms, of which the best known are circadian rhythms, are required for normal physiology of the kidneys and other organs. Chronodisruption refers to the chronic disruption of circadian rhythms leading to disease. While there is evidence that circadian rhythms may be altered in kidney disease and that altered circadian rhythms may accelerate chronic kidney disease (CKD) progression, there is no comprehensive review on chronodisruption and chronodisruptors in CKD and its manifestations. Indeed, the term chronodisruption has been rarely applied to CKD despite chronodisruptors being potential therapeutic targets in CKD patients. We now discuss evidence for chronodisruption in CKD and the impact of chronodisruption on CKD manifestations, identify potential chronodisruptors, some of them uremic toxins, and their therapeutic implications, and discuss current unanswered questions on this topic.
Highlights
The Growing Global Health Burden of Chronic Kidney DiseaseChronic kidney disease (CKD) is currently defined as abnormalities of kidney structure or function, present for longer than 3 months, with implications for health [1]
We review evidence for chronodisruption, its causes and consequences in chronic kidney disease (CKD)
We review the basics of internal clocks and circadian rhythms, the concept of chronodisruption and how this concept applies to CKD leading to the identification of kidney and central chronodisruptors characteristic of the CKD situation and how this may change our approach to CKD management
Summary
Chronic kidney disease (CKD) is currently defined as abnormalities of kidney structure or function, present for longer than 3 months, with implications for health [1]. The increasing burden of CKD at a time when other major causes of death are decreasing should be viewed in the context of the paucity of new therapeutic options that have become available in recent years, when compared, for example, with the cancer field [8] This points towards major deficiencies in our understanding of the pathogenesis of CKD and of the pathophysiology of the CKD-associated increase in cardiovascular risk and premature aging. A key feature of advanced CKD is accumulation of uremic toxins that are no longer excreted by damaged kidneys, in some instances increased toxin production contributes to CKD manifestations [9,10,11] This would not explain why there is already an increased risk of death when GFR is preserved, i.e., in patients in whom CKD is diagnosed because of abnormally high albuminuria yet GFR is still above 60. We review the basics of internal clocks and circadian rhythms, the concept of chronodisruption and how this concept applies to CKD leading to the identification of kidney and central chronodisruptors characteristic of the CKD situation and how this may change our approach to CKD management
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