The association between circadian syndrome and chronic kidney disease in an aging population: a 4-year follow-up study

Throughout history, scholars and researchers have diligently investigated the correlation between the circadian clock system and both diseases and individuals’ physiological states (1). The term “circadian syndrome (CircS)” is employed to denote the phenomenon through which living organisms, spanning multiple hierarchical levels, from molecules and cells to organisms and populations, have undergone adaptive evolutionary processes resulting in the emergence of periodic fluctuations in their life activities as a response to diurnal oscillations in their environmental conditions (2). The concept of CircS is grounded in compelling evidence that several chronic disorders, including obesity, hypertension, dyslipidemia, type 2 diabetes, depression, sleep disorders, and nonalcoholic fatty liver disease, are strongly associated with circadian rhythms (3). CircS serves as the principal regulator influencing nearly every facet of human health and metabolism (1). Various physiological parameters within the human body, encompassing metrics such as pulse rate, body temperature, blood pressure, physical endurance, emotional states, cognitive function, metabolism, organ function, hormone secretion, immunity, and the cell cycle, exhibit periodic fluctuations synchronized with diurnal and nocturnal shifts (4–6).

The central pacemaker of the circadian clock resides within the suprachiasmatic nucleus (SCN) of the brain and synchronizes with external cues, primarily light (2). The central clock synchronizes peripheral clocks located in various regions of the brain and tissues throughout the body, utilizing both neuronal and humoral signaling pathways. While light holds dominance as the Zeitgeber for central clock entrainment, metabolic cues are likely to function as supplementary Zeitgebers for peripheral clocks, particularly those situated in the liver and kidneys (4, 7). It has been confirmed that the kidneys exhibit circadian rhythms, with functions such as urine volume, glomerular filtration rate (GFR), sodium excretion, renal plasma flow (RPF), urine protein excretion rate, urine electrolyte excretion rate, blood pressure, glucocorticoids, erythropoietin, endothelin, and others showing circadian variations (7–10). Chronic kidney disease (CKD) is an umbrella term for various kidney diseases characterized by irreversible structural and functional abnormalities lasting for several months (11). The prevailing criteria employed in the adult population for defining CKD encompass: (1) evidence of kidney impairment, frequently identified through an elevated urine albumin (or protein)-to-creatinine ratio (ACR); or (2) diminished kidney function, characterized by a GFR below 60 ml/min per 1.73 m². GFR is considered the best determinant of kidney function (12). CKD’s main causes vary by region, with diabetes being a leading factor in white individuals, while glomerulonephritis plays a significant role in Asia, but microvasculature dysfunction is a common underlying mechanism (13).

Currently, there is increasing evidence suggesting that modern lifestyles (such as sleep deprivation, lack of physical activity, high-energy diets, and shift work) and the use of artificial lighting can disrupt circadian rhythms, leading to various health consequences and potentially being important factors in the development of CKD (3, 14). Daily rhythmicity is essential for optimal kidney function, as the kidney houses one of the most active peripheral clocks. Disruptions in circadian rhythms have been linked to the onset of CKD in both human studies and animal models (15). Studies by Knutson et al. (16) reported an association between poor sleep quality and lower estimated glomerular filtration rate (eGFR) and higher urine protein to creatinine ratio (PCR) in patients with mild to moderate CKD. A cross-sectional study involving Chinese participants also found an association between poor sleep quality and higher odds of being at high risk for CKD and proteinuria (17). Additionally, cardiovascular events such as arrhythmias and acute myocardial infarctions, as the leading causes of death in CKD patients, also exhibit circadian rhythm characteristics, with higher incidences occurring at night and in the early morning (18). Conversely, CKD can further exacerbate circadian rhythm disturbances. A study in Spain showed that CKD patients had a higher proportion of disrupted blood pressure circadian rhythms, and this condition increased the risk of entering end-stage renal disease (ESRD) (19). In addition, some scholars have found that hemodialysis patients experience circadian rhythm disruption in peripheral tissues, manifesting as diminished nocturnal sleep quality, increased daytime sleepiness, and alterations in circadian biomarkers, such as melatonin (20).

Therefore, CircS may be considered a new cluster of risk factors for chronic kidney disease. However, there is currently no research indicating the relationship between CircS and CKD. The purpose of this study is to use data from the China Health and Retirement Longitudinal Study (CHARLS) to address this question.

To the best of our knowledge, this is the first study to examine the longitudinal association between CircS and CKD among the elderly population aged over 40 years in Chinese communities using nationally representative data. In this population-based prospective cohort study, we observed a positive association between CircS and CKD in the cross-sectional analyses. After a 4-year follow-up period, newly developed CKD was significantly associated with CircS.

Previous research on CircS and CKD has primarily concentrated on specific behaviors, such as irregular or short-duration sleep, shift work, and exposure to artificial lighting (26). Fewer studies have utilized the concept of CircS to categorize individuals and investigate its relationship with health outcomes. Regarding the relationship between sleep duration and physical health issues, numerous studies have demonstrated that individuals who sleep for a short duration (< 6 hours per night) have an elevated risk of hypertension (RR 3.59, 95% CI 1.58-8.17) and CKD (RR 1.63, 95% CI 1.28-2.08) when compared to those who report sleeping 7 hours per night (15, 27, 28). A cohort study indicated a significant association between long-term night shift work and early kidney dysfunction in steelworkers (29). Another observational study found that a minor increase in albuminuria, which serves as an indicator of kidney damage, was linked to the disruption of circadian rhythms caused by shift work, rather than exposure to low levels of nephrotoxic chemicals (30). Concurrently, epidemiological investigations have revealed a higher prevalence of CKD among individuals with either excessively long or short sleep duration, with 7-8 hours of sleep being considered more appropriate (31). Follow-up studies of CKD patients have also shown that those who experience sleep deprivation or deteriorating sleep quality tend to experience a faster decline in eGFR and are more susceptible to progressing to ESKD (32). Additionally, a prospective and longitudinal study involving CKD patients demonstrated that depressive symptoms at baseline are linked to progression to ESRD, mortality, or hospitalization in CKD patients (33). In our study, we also found a longitudinal association between CircS and incident CKD, providing more evidence in this topic. However, this study was performed in the aging Chinese individuals, needing further verification in the overall population.

In our study, baseline survey results indicated that individuals in the CircS group tended to be older, female, divorced/separated/widowed, illiterate, less likely to smoke and drink alcohol, but had higher BMI, LDL, total cholesterol, CRP, uric acid, and hemoglobin levels. They also had a higher prevalence of depression, reduced sleep duration, and hypertension. It may be speculated that women experiencing menopause, shorter sleep duration, and depression are at a higher risk of CKD. However, surprisingly, subgroup analysis revealed an increased risk of prevalent CKD among married or cohabiting participants. This suggests that divorce, separation, or widowhood may play a protective role. One could hypothesize that these life changes might alleviate certain stressors such as family disputes, household responsibilities, or unhealthy relationships, while also prompting individuals to pay greater attention to their health and adopt healthier lifestyles. These factors may collectively contribute to a reduced risk of CKD. It’s important to emphasize that our study is observational in nature and cannot establish causation. Additionally, the relationship between these factors and CKD may be influenced by other underlying variables, necessitating further research for a deeper understanding of this association.

One fundamental assumption explaining these associations is the potential misalignment between external behavioral patterns and endogenous molecular circadian clocks. Kidneys possess peripheral circadian clocks that facilitate the self-sustained rhythmicity of the glomerular filtration rate (29). Studies have demonstrated that the mammalian circadian system operates as a hierarchical multi-oscillator structure (34). The central clock, situated in the SCN of the hypothalamus, orchestrates peripheral clocks distributed throughout the body (2). Given that light serves as the primary external cue for synchronizing the central circadian clock in the SCN (29), it is reasonable to hypothesize that chronic circadian disruption resulting from factors such as shift work, irregular sleep patterns, or artificial lighting may exert an influence on peripheral oscillators, potentially leading to a decrease in eGFR. Another plausible mechanism through which CircS may contribute to declining eGFR involves the presence of psychological and psychosocial stressors (35). Stress can induce renal vasoconstriction by stimulating the sympathetic nervous system, resulting in reduced RPF and GFR (29). Furthermore, persistent activation of the hypothalamic-pituitary-adrenal axis due to chronic external stressors associated with CircS can activate the sympathetic nervous system. Activation of the renal SNS, in turn, may impact renal function through the renin-angiotensin-aldosterone system (RAAS) (36). It has been observed that individuals with sleep disorders exhibit heightened daytime sympathetic nervous system activity (37) and fail to enhance cardiac vagal tone during the transition from wakefulness to non-rapid eye movement (38). Moreover, the overactivation of the RAAS not only leads to an increase in intra-glomerular pressure but also damages vascular endothelial cells, activates reactive oxygen species (ROS), and inhibits sympathetic hyperactivity and nitric oxide (NO), all of which are well-established risk factors for renal damage (39, 40).

Furthermore, canonical clock genes such as Clock, Bmal1, Rev-erbα, Cry1, Cry2, Per1, and Per2 exhibit cyclical expression and/or activity within cells, driving cell-autonomous circadian rhythms (8, 41, 42). Clock genes play a crucial regulatory role in the inflammatory response, and therefore (43), CircS may lead to systemic inflammation, which could result in endothelial dysfunction within glomeruli and subsequent renal impairment, thereby promoting CKD progression. For instance, the circadian clock protein BMAL1 regulates interleukin-1β (IL-1β) in macrophages through the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway (44). Nrf2 expression is upregulated in the glomeruli of lupus nephritis (LN) patients, and in LN mouse models, Nrf2 mitigates LN by inhibiting oxidative injury and the NF-κB-mediated inflammatory response (45). Additionally, hypertension is a significant etiological factor for CKD development and progression (46), particularly with mean sleep systolic blood pressure recognized as one of the most important independent predictors of CKD (47). For every one standard deviation decrease in mean sleep systolic blood pressure, the risk of CKD decreases by 27% (48). Normal blood pressure exhibits a clear circadian rhythm, with elevated blood pressure upon awakening in the morning and a decrease during nocturnal sleep (41, 49). This rhythmicity is regulated by various factors with circadian patterns, including environmental cues, the nervous system, the hypothalamus-pituitary-adrenal axis, vascular factors, and the kidneys (49). Consequently, disruptions in circadian rhythms that lead to non-dipping nocturnal blood pressure (non-dipper hypertension) are associated with the occurrence and progression of CKD, although the underlying molecular mechanisms remain unclear (50, 51).

The limitations of this study include the lack of repeated measurements for CircS and some potential covariates. Additionally, the follow-up period was relatively short, and a 4-year follow-up may not be sufficient to detect more pronounced effects of CircS. All sleep information was collected through self-reports, which may be subject to recall bias and misclassification, rather than objective measurements of sleep parameters. Future research should focus on objective sleep monitoring methods, such as polysomnography (52), wrist actigraphy and sleep diaries (31). Non-alcoholic fatty liver disease (NAFLD) was initially proposed as a component of CircS (53). It is well-known that the prevalence of NAFLD in China is high (approximately 20%) (54). However, we did not have information about NAFLD in our study. Finally, because our study participants were Chinese, the generalizability of our findings may be limited by ethnic differences. Future research should examine whether our findings can be applied to other populations. Despite these limitations, our study had a large sample size, was nationally representative, had a high follow-up rate, and collected detailed data for each participant. Furthermore, we adjusted for a wide range of covariates to explore the independent influence of CircS on the incidence of CKD.

In summary, our study was conducted in a middle-aged and elderly Chinese population and provided evidence that CircS is a risk factor for CKD. However, the mechanisms by which CircS leads to CKD require further investigation.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

The ethical review board of Peking University meticulously examined and subsequently sanctioned this study (IRB 00001052-11014). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

YX: Writing – original draft, Visualization, Software, Methodology, Formal Analysis. QZ: Writing – original draft, Formal Analysis, Conceptualization. YZ: Writing – review & editing, Software, Project administration, Methodology, Formal Analysis. ZL: Writing – review & editing, Supervision, Project administration, Methodology, Conceptualization. XW: Writing – review & editing, Supervision, Project administration, Funding acquisition, Conceptualization.

The authors sincerely thank the authors who shared the original dataset in this study.

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the 1.3.5 Project for Disciplines of Excellence-Clinical Research Incubation Project, West China Hospital, Sichuan University (No. 2021HXFH007), and Sichuan Science and Technology Program (No. 2023YFS0256).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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