*Review* **Chronodisruption: A Poorly Recognized Feature of CKD**

**Sol Carriazo 1,2, Adrián M Ramos 1,2, Ana B Sanz 1,2, Maria Dolores Sanchez-Niño 1,2, Mehmet Kanbay 3 and Alberto Ortiz 1,2,\***

1 IIS-Fundacion Jimenez Diaz, Department of Medicine, Universidad Autonoma de Madrid, Fundacion Renal Iñigo Alvarez de Toledo-IRSIN, 28040 Madrid, Spain; sol.carriazo@quironsalud.es (S.C.); amramos@fjd.es(A.MR.);asanz@fjd.es(A.BS.);mdsanchez@fjd.es(M.D.S.-N.)


Received: 30 January 2020; Accepted: 20 February 2020; Published: 28 February 2020

**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.

**Keywords:** chronodisruption; chronodisruptor; circadian rhythm; internal clock; chronic kidney disease

**Key Contribution:** Chronodisruption refers to the chronic disruption of circadian rhythms leading to disease. We now review evidence for chronodisruption, its causes (chronodisruptors) and consequences in chronic kidney disease (CKD).

### **1. Introduction: The Growing Global Health Burden of Chronic Kidney Disease**

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 abnormalities of kidney structure or function may be recognized by several criteria. Just one of these criteria is enough to diagnose CKD. The most commonly used criteria are the ones that characterize CKD categories: An abnormal function defined by a decreased glomerular filtration rate (GFR, <60 mL/min/1.73 m2, that is, G categories G3–G5) or evidence of kidney damage such as albuminuria (albumin excretion rate ≥ 30 mg/<sup>24</sup> h; urinary albumin creatinine ratio ≥ 30 mg/g, that is, A categories A2 or A3). As for the concept of "implications for health", it reflects the fact that CKD is associated with an increased risk of all-cause or cardiovascular death, of CKD progression and of development of acute kidney injury (AKI). In this regard, the contribution of CKD to the global disease burden has increased sharply in recent decades. CKD is estimated to become the fifth global cause of death by 2040 and in countries with long life expectancies, it has been projected to become one of the two top causes of death before the end of the century [2,3]. The increasing contribution of CKD to the global burden of disease can be traced to several causes. On one hand, age-adjusted mortality for some key causes of death is actually decreasing. On the other, the longer life expectancy of the population and the increasing prevalence of risk factors for CKD such as obesity, diabetes and hypertension, together with the underdeveloped therapeutic armamentarium, are driving up the prevalence and impact of CKD. There is hope in the recent characterization of a dramatic nephroprotective impact of sodium-glucose transport protein 2 (SGLT2) inhibitors when added on top of renin angiotensin system (RAS) blockade for diabetic kidney disease and potentially other kidney diseases [4–6]. However, data from the hypertension field have clearly demonstrated that the availability of e ffective drugs is not enough, especially in polymedicated populations, where guidelines now emphasize measures to facilitate compliance [7]. In any case, 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, although in some instances increased toxin production also contributes to CKD manifestations [9–11]. However, 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 ye<sup>t</sup> GFR is still above 60 mL/min/1.73 m2. Additional pathogenic events have been recently identified in these patients, such as loss of the kidney production of the anti-aging factor Klotho [12]. A long-recognized feature of CKD is an alteration of well characterized circadian rhythms, including circadian changes in blood pressure and urine concentrating ability. The widespread use of 24 h ambulatory blood pressure monitoring has familiarized physicians with the concept of the sleep time dip of blood pressure and the lack of such dip in CKD patients: CKD patients are characteristically non-dippers [13]. However, the molecular basis of this altered blood pressure circadian rhythm and the existence of other altered rhythms as well as the consequences of these altered rhythms for CKD progression and CKD-associated morbidity and mortality are less well known. We now 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.
