Association Among Sleep, Depression, And Health-related Quality Of Life in Patients With Non-dialysis Chronic Kidney Disease During The Coronavirus Disease 2019 Pandemic

Discussion 

In this cross-sectional study of patients with non-dialysis CKD, we verified important associations of self-reported sleep with depression as well as HRQOL and had some major discoveries. First, the overall prevalence of sleep disturbance was 58%, meaning that more than half of the non-dialysis CKD population suffered from poor sleep during the COVID-19 pandemic. Second, sleep disorders were associated with increasingly poor HRQOL and depressive symptoms. Third, depression mediated the effects of sleep disturbance on the PCS and MCS of HRQOL in non-dialysis CKD patients.

CISTANCHE EXTRACT WITH 30% ECHINCAOSIDE FOR KIDNEY DISEASE

Table 2 Depression and HRQOL scores according to sleep status

Table 3 Linear regression between HRQOL, depression, and sleep in CKD

Univariate and multivariate linear regression models were employed in analyses, and the multivariate model included variables significantly associated with the above areas in the univariate analysis. a, The model is adjusted for a place of residence, education, monthly income, CKD diagnosis time, and anemia; b, The model is adjusted for age, place of residence, diabetes, and hyperuricemia; c, The model is adjusted for education, monthly income, diabetes, anemia, hormone use and eGFR; d, The model is adjusted for monthly income; e, The model is adjusted for place of residence, education, employment status, monthly income, anemia, hyperuricemia, hyperlipidemia, hormone use and eGFR. f, the model is adjusted for hyperuricemia and hormone use. HRQOL, health-related quality of life; CKD, chronic kidney disease; CI, confidence interval; PCS, physical component summary; MCS, mental component summary; PHQ-9, 9-item Patient Health Questionnaire.

In prior reports of CKD patients not on dialysis, the overall prevalence of sleep disturbances was between 20‒40% (20-22). The proportion of PSQI global score >5 in our study was higher than the rates, suggesting a significant increase in the incidence of sleep disorders during the COVID-19 pandemic. That is, the COVID-19 pandemic hurt the sleep of non-dialysis CKD, which was in accord with studies of other populations (23).

Figure 1 Mediation effects of depression on sleep and HRQOL. *, P<0.05; **, P<0.01; ***, P<0.001. PM, mediation proportion; βc, total effect; βc', direct effect; CI, confidence interval; HRQOL, health-related quality of life.

In our study, distinctions in sleep among patients with non-dialysis CKD were explained largely by age, anemia, and glucocorticoid use, similar to the results reported in previous studies (19,24-26). A large-scale study found that time-in-bed and total sleep time showed a U-shaped association with age, which further corroborated the reliability of our results (27). Anemia, a common complication of CKD, contributes to sleep issues frequently (28). This could be explained by several factors: iron deficiency impairs certain neurotransmitters needed for sleep, such as norepinephrine, serotonin, and dopamine. In the meantime, anemia might disrupt sleep by causing restless legs syndrome, a symptom widely present in CKD patients (29). Glucocorticoids, the final mediators of the hypothalamic-pituitary-adrenal axis cascade, are critical to the pathogenesis of sustained stress-related sleep disorders (30). However, our data indicated the use of glucocorticoids was beneficial for sleep, possibly because glucocorticoids ease the pain of the disease, leading to improved sleep. Meanwhile, different from several studies (19,31) which have reported that females and those with lower eGFR in dialysis patients are more susceptible to poor sleep, our results suggested that there were no differences in gender or eGFR between good sleepers and poor sleepers. The most likely reason for this is the difference in the subjects studied. Several additional factors we didn't consider may also influence sleep situations. According to the reports, there is a complex interaction between inflammatory markers and sleep. Some inflammatory cytokines could affect sleep-wake regulation (32-34), while sleep deprivation increases inflammatory reactivity (35-37). The regression model adjusted for critical factors in a cross-sectional study showed that constipation-related symptoms were independently associated with the incidence of sleep disorders (38). Moreover, different treatments and side effects of medications such as calcium channel blockers have impacts on sleep (39,40). Patients with sleep disturbance had over four times the prevalence of depression and a global reduction in HRQOL when compared with those without sleep disorders, indicating increased distress of poor sleepers. The results of multiple linear regression models revealed that the psychological status and HRQOL of good sleepers remained better even after adjustment for demographic and clinical variables. The strong correlation between sleep disturbance and depression, as well as HRQOL in patients with CKD not on dialysis, paralleled prior discoveries of the link seen between impaired sleep quality and these self-reported outcomes in dialysis patients. 

Previous research has demonstrated that there is a high comorbidity between sleep disturbance and depression (41-43). Recently, the directional relationship of the two has been extensively explored. A longitudinal study reported by Breslau et al. supported that sleep disorders were likely to precede depression, not the other way around (44). Meta-analyses have suggested poor sleep is recognized as a frequent precursor to the development of depression (45). Many other studies have also proved this view by building models such as the structural equation model and cross-lagged panel model (46,47). Meanwhile, the strong correlation between depression and HRQOL led to depression often playing a mediating role in the relationship between certain factors and HRQOL. For example, depression could mediate the impact of clinical pain on HRQOL in fibromyalgia (48), as well as the effect of seizure frequency on HRQOL in patients with epilepsy (49). Most importantly, psychological disturbance played a mediating role in the relationship between sleep disturbance and HRQOL in patients on dialysis (50). Based on the above studies and what we've proven about the relationship between the three, we hypothesized and examined whether depression mediated the association between sleep status and HRQOL in patients with non-dialysis CKD. The results suggest that depression significantly mediates the relationship between sleep and HRQOL, which may be explained by a working mechanism of a physio-psycho-physiological cycle. Depression could be a psychological trigger for HRQOL and sleep is a significant factor in tipping the trigger. Sleep disorders and depression share a bidirectional relationship that reinforces each other, which ultimately leads to a decline in HRQOL (51,52). These conclusions underscore the importance of symptom management on HRQOL. Future studies of sleep and psychological interventions among people with non-dialysis CKD should be a priority.

Several limitations are worth noting. First, the generalizability of the results might be weakened due to the relatively small sample size. Second, polysomnography and actigraphy, which monitor sleep situations objectively, were not employed in this research. Instead, we relied solely on patients' self-reports. Third, depressive symptoms and sleep disorders were defined as self-reported questionnaire scores above selected cut-offs, therefore we can't make a clinical diagnosis. Fourth, some information related to the COVID-19 outbreak was not assessed because of the lack of standardized questionnaires, such as whether they had difficulty in hospitalizing for the COVID-19 pandemic restrictions. Finally, the cross-sectional analysis of the study made it impossible to draw causal conclusions between sleep disturbances and other variables (23).

In conclusion, our data showed the high prevalence of sleep disturbances as well as the strong associations between sleep disorders, depressive symptoms, and HRQOL in patients with non-dialysis CKD during the COVID-19 pandemic. Therapy of the underlying diseases has only partial effects on HRQOL in patients with CKD, therefore, attention should be paid to treatable health-related domains such as sleep and depression. Future prospective, interventional studies may assess the potential contribution of drugs to sleep and psychology, as well as the benefits of relevant treatment regimens on patient health outcomes. Nephrologists should be aware of the severity of sleep disturbance and depression in patients with nondialysis CKD and consider screening patients for poor sleep and mental health to find out who might benefit from treatments that may provide relief (53,54), with the ultimate objective of improving the HRQOL, especially during the COVID-19 pandemic. 

Acknowledgments 

Funding: This work was supported by grants from the Natural Science Basic Research Plan in Shaanxi Province of China (No. 2019JM-033); Technology Innovation Development Foundation of Tangdu Hospital (Nos. 2019QYTS003, 2020XKPT014 and 2021QYJC-001); and Nursing Research Foundation of Tangdu Hospital (No. TDHLKY-2019-05). Footnote Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://apm. amegroups.com/article/view/10.21037/apm-21-3416/rc Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm. amegroups.com/article/view/10.21037/apm-21-3416/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted by the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Tangdu Hospital (No.: TDLL-202201-01) and informed consent was taken from all the patients. Open Access Statement: This is an Open Access article distributed by the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the noncommercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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