Sleep Medicine 51 (2018) 59e65

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Sleep Medicine
journal homepage: www.elsevier.com/locate/sleep

Review Article

Association of sleep disorders, chronic pain, and fatigue with survival

in patients with chronic kidney disease: a meta-analysis of clinical
trials
Xiu Hong Yang a, 1, Bao Long Zhang b, 1, Yan Hong Gu a, Xiao Li Zhan a, Li Li Guo c,
Hui Min Jin a, *
a
Division of Nephrology, Shanghai Pudong Hospital, Fudan University, Pudong Medical Center, Shanghai, China
b
The Institutes of Biomedical Sciences (IBS), Fudan University, Shanghai, China
c
Hemodialysis Center, Bao Shan Branch of No.1 People's Hospital, Shanghai Jiao Tong University, Shanghai, China

a r t i c l e i n f o a b s t r a c t

Article history: Objective: Sleep disorders, chronic pain, and fatigue have been long-standing torments in most patients
Received 16 April 2018 with chronic kidney disease (CKD). In this review, we attempted to explore whether these nontraditional
Accepted 2 June 2018 cardiovascular risk factors are associated with increased mortality in patients with CKD.
Method: Electronic searches were performed in MEDLINE (PubMed, 1966e2018), EMBASE (1974e2018),
ClinicalTrials.gov, and the Cochrane Central Register of Controlled Trials databases. All prospective or
Keywords:
retrospective studies were considered eligible if they were cohort or observational studies and the final
Sleep disorders
outcome was all-cause death or mortality.
Chronic pain
Fatigue
Results: We ultimately included 18 studies (12 studies on sleep disorders, three studies on chronic pain,
Chronic kidney disease (CKD) and three studies on fatigue) in our review. Pooled analysis of all studies indicated that patients with
Meta-analysis sleep disorders, chronic pain, and fatigue had increased risks of all-cause mortality (risk ratio [RR] ¼ 1.47,
95% confidence interval [CI] ¼ 1.30e1.66, p < 0.0001; RR ¼ 1.29, 95% CI ¼ 1.27e1.31, p < 0.0001;
RR ¼ 1.45, 95% CI ¼ 1.23e1.70, p < 0.0001, respectively). Pooled results from four studies indicated that
dialysis patients with sleep-disordered breathing had increased cardiovascular disease outcomes
(RR ¼ 2.45, 95% CI ¼ 1.74e3.44, p < 0.0001).
Conclusion: Sleep disorders, chronic pain, and fatigue are remarkably associated with increased all-cause
mortality in patients with CKD. Large clinical randomized controlled trials are required to further confirm
the results of our meta-analysis.
© 2018 Elsevier B.V. All rights reserved.

1. Introduction efficiency at night, excessive daytime sleepiness, periodic limb

Patients with chronic kidney disease (CKD), especially those on
hemodialysis (HD), are at high risk for various complications, such as
cardiovascular disease (CVD), bleeding and ischemic stroke, hyper-
tension, and bone mineral metabolic disorders [1e3]. However,
some clinical manifestations and symptoms such as sleep disorders,
chronic pain, and fatigue often exert negative effects on these pa-
tients. Sleep disorders, including reduced sleep duration and sleep
* Corresponding author. Division of Nephrology, Shanghai Pudong Hospital,
Fudan University, Pudong Medical Center, 2800 Gong Wei Road, Shanghai, China.
E-mail address: hmjgli@163.com (H.M. Jin).
1 the association of sleep disorders, chronic pain, and fatigue with
Xiu Hong Yang and Bao Long Zhang contribute equally to this work.
movements in sleep, sleep-disordered breathing (SDB), and sleep
apnea syndrome, occur with increased frequency in patients with
CKD. It has been reported that 80% of dialysis patients with CKD are
affected by sleep disorders. These patients have short, fragmented
sleep with a total sleep duration between 260 and 360 min and
sleep efficiencies between 66% and 85% [4]. Chronic pain and fatigue
are significant factors associated with CKD that have received
increasing recognition in recent years and commonly result in
increased depression and diminished quality of life. To date, some
small clinical trials have assessed whether sleep disorders, chronic
pain, and fatigue are associated with survival in patients with CKD
or HD patients; however, these studies have reported inconsistent
results [5e22]. Considering these inconsistent results in regard to

https://doi.org/10.1016/j.sleep.2018.06.020
1389-9457/© 2018 Elsevier B.V. All rights reserved.
60 X.H. Yang et al. / Sleep Medicine 51 (2018) 59e65
survival in dialysis or nondialysis patients with CKD, we believe that
it is important to attempt to resolve the issue. Therefore, we con-
ducted a meta-analysis of published clinical trials to pool the results
and, thus, improve the statistical power of the analysis.
2. Methods
2.1. Search strategy
The relevant literature was searched in MEDLINE (PubMed,
1966e2018), EMBASE (1974e2018), ClinicalTrials.gov, and
Cochrane Central Register of Controlled Trials databases using the
following terms: “sleep OR pain OR fatigue” AND “chronic kidney
disease (CKD) OR end stage renal disease (ESRD)” AND “all-cause
death OR all-cause mortality OR survival OR mortality.” Manual
searches of references cited by the identified original studies and
relevant review articles were attempted. All studied papers were on
human subjects and were published in the English language. The
detailed steps are presented in Fig. 1. A total of 18 studies were
included in our meta-analysis, which are listed in Tables 1 and 2.
These 18 studies met the following inclusion criteria adopted for
our meta-analysis: duration of more than six months; average
patient age of less than 75 years; use of a control group; and
availability of outcome data on mortality in patients with CKD.
2.2. Data collection
Three reviewers (H,M.J., X.H.Y., B.L.Z.) performed the search and
reviewed the results. Data were collected by all authors and inde-
pendently extracted by three reviewers (H.M.J., H.X.Y., B.L.Z.), who
reviewed all the study characteristics (ie, first author's surname,
year of publication, study design, sample, follow-up, outcomes, and
assessment of study quality). Any disagreement in data extraction
was resolved through a discussion between these two reviewers in
consultation with the other authors (H.Y.G., X.L.Z., L.L.G.).
2.3. Quality assessment for individual studies
The two previously mentioned reviewers assessed the quality of
each selected study using the NewcastleeOttawa Scale [23], which
assigns a maximum of nine stars to a study based on the quality of
patient selection, study design, comparability, exposure, and
Fig. 1. Study selection process.
outcome. We considered a study to be of “high quality” if it scored
nine stars on this scale and “medium quality” if it scored seven or
eight stars. Any discrepancies were resolved through a discussion
between these two reviewers.
2.4. Summary measures and synthesis of results
The risk ratios (RRs) for sleep disorders, chronic pain, and fa-
tigue associated with mortality were extracted from each study or
calculated by a reviewer (X.H.Y.). Four studies reported that sleep
disorders are associated with CVD outcomes; thus, we used sub-
group analysis to assess the effect of sleep disorders on the relative
risk of CVD. We provided the following baseline characteristics of
all included studies: study design, method(s) of assessment, sub-
jects, mean follow-up time, age, sex, pre-existing conditions, out-
comes, and quality. To assess the potential for publication bias, we
constructed funnel plots for each outcome in which the log RRs
were plotted against their standard errors. We also conducted a
sensitivity analysis in which each study was extracted in turn to
evaluate the effect of the study on the estimate.
2.5. Statistical analyses
Risk ratios represented a valid approach to assess the risks of
mortality associated with sleep disorders, chronic pain, and fatigue.
Statistical heterogeneity across various studies was tested using
Cochran's Q test. A p value of more than the nominal level of 0.05
indicated a lack of heterogeneity across the studies. Because the
studies used a variety of assessments of sleep disorders, pain, and
fatigue, which would lead to heterogeneity, RRs and 95% confi-
dence intervals (CIs) were calculated using a random effects model.
We also performed subgroup analysis to evaluate the association of
sleep disorders with CVD outcomes. We used the Egger test to
examine the presence of publication bias. Data were analyzed using
STATA 14.0 (StataCorp, College Station, TX, USA). Statistical signif-
icance was set at p < 0.05 for all analyses.
3. Results
3.1. Study flow and study characteristics
The decision process that was used to differentiate the studies
considered for inclusion is displayed in Fig. 1. Overall, as previously
mentioned, we ultimately included 18 studies (12 studies on sleep
disorders, three studies on chronic pain, and three studies on fa-
tigue). Table 1 shows the characteristics of the 12 included studies
on sleep disorders. All studies recorded all-cause mortality, and
four studies recorded CVD outcome. Of the selected clinical trials,
nine and three focused on dialysis and nondialysis patients,
respectively. Table 2 presents the characteristics of the six studies
on chronic pain and fatigue associated with mortality. All studies
recorded all-cause mortality; of the selected clinical trials, five and
one focused on dialysis and nondialysis patients, respectively. The
results of quality assessment indicated that 11 and seven studies
were of high and medium quality, respectively. The seven medium-
quality studies lacked detailed descriptions of the study design.
3.2. Association of mortality with sleep disorders, chronic pain, and
fatigue in patients with CKD
Exploratory data analysis of all studies indicated that patients
with sleep disorders, chronic pain, and fatigue had increased risks
of all-cause mortality, as shown in Figs. 2e4 (RR ¼ 1.47, 95%
CI ¼ 1.30e1.66, p < 0.0001; RR ¼ 1.29, 95% CI ¼ 1.27e1.31,
p < 0.0001; RR ¼ 1.45, 95% CI ¼ 1.23e1.70, p < 0.0001, respectively).
 X.H. Yang et al. / Sleep Medicine 51 (2018) 59e65 61

Table 1
Characteristics of 12 studies associated of mortality with sleep disorders in the chronic kidney disease (CKD) population.

Study authors, Study design Methods of assessment Participants Mean Age (y) Sex (% Pre-existing Outcomes Quality
reference, year (n) follow-up male) conditions
(mo)

Sleep duration and quality

Unruh et al. [5], Prospective CHOICE Health Experience 909 12 57.8 ± 14.8 53.1 Hemodialysis and All-cause High
2006 cohort Questionnaire peritoneal dialysis death
Iseki et al. [6], Prospective Japanese version of the Epworth 1252 36 63.5 ± 12.1 61.4 Hemodialysis All-cause High
2015 cohort (DOPPS) Sleepiness death
Scale (JESS)
Ricardo et al. [7], Prospective Activity monitor, Pittsburgh Sleep 431 60 59.7 ± 10.4 51.7 CKD All-cause High
2017 observational Quality death
Index (PSQI), and Epworth Sleepiness
Scale (ESS)
Ricardo et al. [8], Prospective Sleep Heart Health Study Sleep Habits 1452 53 60.4 ± 0.8 41.4 CKD All-cause High
2017 cohort Questionnaire and the Functional death
Outcomes of Sleep Questionnaire
Periodic limb movement in sleep (PLMS)
Benz et al. [9], Observational Polysomnography and Semi-Automatic 29 48 58.7 ± 12.7 62.1 Hemodialysis All-cause Medium
2000 Sleep death
Scoring System, PLMS
Jung et al. [10], Observational Polysomnography (a validated recording 30 48 55.8 ± 10.6 70.0 Hemodialysis All-cause Medium
2010 unit, death
Embla System), PLMS
Sleep disordered breathing (SDB)
Argekar et al. Observational Flemons criteria questionnaire 270 34 60.1 ± 16.2 N/A Hemodialysis CVD; all- Medium
[11], 2007 cause death
Tang et al. [12], Prospective Apneahypopnea index (AHI) 51 41 55.3 ± 14.5 51.6 Peritoneal dialysis CVD; all- High
2010 cohort cause death
Masuda et al. Observational Wristwatch-type pulse oximetry 94 55.1 64.4 ± 1.3 53.2 Hemodialysis CVD; all- High
[13], 2011 (PULSOX-M24), cause death
oxygen desaturation index (ODI), and
Epworth Sleepiness Scale (ESS)
Sivalingam et al. Observational Apneahypopnea index (AHI), oxygen 91 44 60.2 ± 14.3 65.9 Hemodialysis All-cause High
[14], 2012 desaturation death
index (ODI), and Epworth Sleepiness
Scale (ESS)
Torino et al. [15], Observational Self-reported Snoring 827 27.6 65.0 ± 14.0 63.4 Hemodialysis and CVD; all- Medium
2014 peritoneal dialysis cause death
Xu et al. [16], Observational Polysomnography (Embla N7000), 1454 30.7 60.6 ± 12.2 72.8 CKD All-cause Medium
2016 apneahypopnea index (AHI), death
respiratory
effortrelated arousal index (RERA),
respiratory
disturbance index (RDI)

CVD, cardiovascular disease; N/A, data not available; PLMS, periodic limb movement in sleep.

Table 2
Characteristics of six studies associated of mortality with chronic pain and fatigue in the chronic kidney disease (CKD) population.

Study author, Study design Methods of assessment Participants Mean follow- Age (y) Sex (% Pre-existing conditions Outcomes Quality
reference, year (n) up (mo) male)

Chronic pain
Harris et al. [17], Observational Modified McGill Pain 128 36 57.3 ± 13.8 60.2 Hemodialysis All-cause Medium
2012 questionnaire (MPQ) death
Weisbord et al. Prospective Short-Form McGill Pain 286 24 64.0 ± 8.5 56.3 Hemodialysis All-cause high
[18], 2014 randomized Questionnaire (SF-MPQ) death
Ravel et al. [19], Retrospective Pain as the fifth vital sign 2,360,056 94 60.0 ± 13.0 94.0 CKD All-cause High
2016 cohort death
Fatigue
Jhamb et al. [20], Prospective cohort 36-Item Short Form (SF-36) 917 12 57.9 ± 14.8 53.1 Hemodialysis and All-cause High
2009 questionnaire peritoneal dialysis death
Jhamb et al. [22], Randomized 36-Item Short Form (SF-36) 1798 34 57.5 ± 14.0 43.7 Hemodialysis All-cause High
2011 controlled questionnaire death
Bossola et al. [21], Cross-sectional Vitality Scale of SF-36 (SF-36 115 43 65.3 ± 13.2 54.0 Hemodialysis All-cause Medium
2015 observational VS) death

3.3. Subgroup analysis of relative risk of CVD in patients with CKD 3.4. Quality of included studies

Pooled results from four studies indicated that dialysis patients All studies scored seven or more stars out of nine stars on the
with SDB had increased CVD outcomes, as shown in Fig. 5 NewcastleeOttawa Scale; the maximum quality of the included
(RR ¼ 2.45, 95% CI ¼ 1.74e3.44, p < 0.0001). studies was moderate, and the CIs for the analyses were narrow.
62 X.H. Yang et al. / Sleep Medicine 51 (2018) 59e65

Fig. 2. Risk ratios (RRs) for all-cause mortality associated with sleep disorders from pooled studies. The estimated RRs were significantly different across 12 studies (RR ¼ 1.47, 95%
confidence interval ¼ 1.30e1.66, p < 0.0001).

Fig. 3. Risk ratios (RRs) for all-cause mortality associated with chronic pain from pooled studies. The estimated RRs were markedly different across three studies (RR ¼ 1.29, 95%
confidence interval ¼ 1.27e1.31, p < 0.0001).

Most studies consistently showed an association of increased (not shown), with asymmetry being formally assessed using the
mortality with sleep disorders, chronic pain, and fatigue in patients Egger test. The results indicated that there was significant publi-
with CKD. cation bias (p ¼ 0.013).

3.5. Sensitivity analysis and publication bias 4. Discussion

Sensitivity analysis indicated that the exclusion of any individ-
ual study from the analysis did not alter the overall conclusions. In
the sensitivity analysis, we considered variance in study design as a
possible source of heterogeneity. The sensitivity analysis could not
adequately explain the heterogeneity; however, we considered that
heterogeneity did not distort our results. Publication bias was
assessed by visually examining a funnel plot of precision against RR
Sleep disorders have a profound and well-documented effect on
overall health and quality of life in the general population. In pa-
tients with CKD, especially in HD patients, sleep disorders are more
prevalent. Poor sleep quality can lead to many complications, such
as CVD and increased mortality in patients undergoing mainte-
nance HD [6,7,17]. In the meta-analysis, we confirm that short sleep
duration or poor sleep quality, periodic limb movements in sleep,
 X.H. Yang et al. / Sleep Medicine 51 (2018) 59e65 63

Fig. 4. Risk ratios (RRs) for all-cause mortality associated with fatigue from pooled studies. The estimated RRs were remarkably different across three studies (RR ¼ 1.45, 95%
confidence interval ¼ 1.23e1.70, p < 0.0001).

Fig. 5. Risk ratios (RRs) for cardiovascular disease (CVD) outcomes with association of sleep-disordered breathing (SDB) with cardiovascular events from pooled studies. The
estimated RRs were significantly different across four studies (RR ¼ 2.45, 95% confidence interval ¼ 1.74e3.44, p < 0.0001).

SDB, and sleep apnea syndrome are strongly associated with
increased mortality in patients with CKD. Factors affecting poor
sleep are probably associated with uremic toxin, pruritus, and so-
cial and financial burden [24,25].
There are several potential explanations for the association be-
tween sleep disorders and increased mortality in patients with
CKD. In healthy young adults, it was shown that sleep restriction
could cause acute increases in blood pressure and heart rate [26],
leading to an increase in salt retention and activation of the sym-
pathetic nervous system [27,28]. In the general population, short
sleep duration has been shown to be associated with increased risk
of incident hypertension, type 2 diabetes, and coronary artery
disease [29]. Dayenight sleep reversal has been proposed to
explain the excessive daytime sleepiness in patients with CKD [30],
as well as subclinical uremic encephalopathy [31], abnormal
metabolism and retention of melatonin [32], alteration in body
temperature rhythm resulting in perturbation of the sleepewake
cycle [33], and release of sleep-inducing proinflammatory cyto-
kines during dialysis [34].
The prevalence rate of SDB in patients with advanced CKD has
been estimated to be more than 50%, and obstructive SDB is the
predominant type in patients with CKD [35]. SDB is an often
overlooked serious public health problem in the population with
CKD. Moreover, SDB is associated with episodic upper airway
obstruction or cessation of breathing during sleep, leading to re-
petitive episodes of hypoxemia, hypercapnia, sleep fragmentation,
activation of the sympathetic nervous system, endothelial
dysfunction, oxidative stress, and inflammation [36]. From a car-
diovascular point of view, SDB is associated with the development
of hypertension, accelerated atherosclerosis, heart failure, and
ischemic stroke in the general population and in patients with CKD
[37]. There are two types of sleep apnea: obstructive sleep apnea
and central sleep apnea. In our meta-analysis, all selected clinical
trials dealt with obstructive sleep apnea, with no study dealing
with central sleep apnea. Whether central sleep apnea is associated
with increased mortality in the population with CKD requires
confirmation in future studies.
Chronic pain is a common problem in HD patients. Pain and
sleep disorders overlap, with chronic pain often affecting sleep.
More than one-fifth of the HD population in the United States re-
ported pain as a troublesome problem [38]. Chronic pain, a marker
of poor health, was associated with depression and sleep problems
in HD patients and could prompt more patients to consider with-
drawal from dialysis [39]. Pain perception could be associated with
increased stress or diminished perception of quality of life and
elevated levels of proinflammatory cytokines in patients with CKD
[40], which have been linked to increased mortality. Moreover, pain
perception could be associated with increased disability or
depression, both of which are associated with mortality. Chronic
pain reciprocally causes stress, leading in turn to the release of
catecholamines and glucocorticoids, inducing an increase in blood
pressure [41].
Fatigue is an important bio-alarm for human health, and is
described as a newly recognized important syndrome (chronic fa-
tigue syndrome). It is one of the most frequent symptoms in HD
patients, and its prevalence rate ranges from 60% to 97% in HD
patients [42]. Data on the effect of fatigue on survival in chronic HD
patients are limited and conflicting [20e22]. From our pooled
64 X.H. Yang et al. / Sleep Medicine 51 (2018) 59e65
results, fatigue is a strong predictor of mortality in HD patients.
Koyama et al., observed that among the eight conceptualized
fatigue-related factors (ie, fatigue itself, anxiety and depression,
loss of attention and memory, pain, overwork, autonomic imbal-
ance, sleep problems, and infection), fatigue itself is the strongest
predictor of cardiovascular events in HD patients; the relative risk
of fatigue for cardiovascular events is around 1.89 (95%
CI ¼ 1.06e3.36, p ¼ 0.02) [43]. The potential mechanisms of the
association of fatigue with survival are probably related to meta-
bolic, hemodynamic, and immune responses involving abnormal
lipid metabolism, decreased fibrinolysis, low heart rate variability,
and higher levels of proinflammatory cytokines, all contributing to
increased risk of cardiovascular events and mortality in the popu-
lation with CKD [43,44].
Our meta-analysis has several limitations that should be clari-
fied. First, there was remarkable heterogeneity across studies on
sleep disorders (I2 ¼ 59.7%, p ¼ 0.004; see Fig. 2) due to variable
data sources and different study designs (prospective and retro-
spective), as well as variable sleep data (sleep duration, periodic
limb movements in sleep, and SDB). Second, although we defined
high-quality studies as those that scored a maximum of nine stars
on the NewcastleeOttawa Scale, many of our high- and medium-
quality studies have not been randomly used, and this could lead
to several biases (eg, selection bias, survival bias, and informative
censoring). Third, there exists publication bias in our meta-analysis
with respect to the association of sleep disorders with mortality in
patients with CKD. Undeniably, positive results are easily pub-
lished; however, in this meta-analysis, there were negative results
as well. Fourth, in the meta-analysis of association of chronic pain
and fatigue with survival, papers were available for analysis,
probably producing inadequate data power. Moreover, other
potentially important factors (eg, residual renal function, intensity
of dialysis, and presence of coexisting diseases) were not reported
in some included studies. Future studies on survival outcomes
should consider these potential confounders.
Despite these limitations, our meta-analysis of 18 controlled
studies shows that sleep disorders, chronic pain, and fatigue are
associated with increased mortality in patients with CKD.
Improving sleep quality, chronic pain, and fatigue in patients with
CKD may positively affect their well-being and survival. Clinicians
must place greater emphasis on these nontraditional cardiovascu-
lar risk factors.
Acknowledgements
This study was supported by the Key Specialized Construction
Project in Medicine of Shanghai (Grant No. ZK2015A15) and Con-
struction of Key Academic Groups in Nephrology in Pudong New
Area (Grant No. PWZxq2017-07). All authors have approved the
final version of the manuscript and have agreed to submit it to this
journal. The authors declare no conflict of interest with respect to
the publication of this article.
Conflict of interest
The authors declare that they have nothing to disclose.
The ICMJE Uniform Disclosure Form for Potential Conflicts of
Interest associated with this article can be viewed by clicking on the
following link: https://doi.org/10.1016/j.sleep.2018.06.020.
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