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REVIEW

CURRENT
OPINION Obstructive sleep apnea and chronic kidney disease
Chou-Han Lin a,b, Elisa Perger c, and Owen D. Lyons a,d,e

Purpose of review
Obstructive sleep apnea (OSA) is highly prevalent in patients with chronic kidney disease (CKD). The
relationship between OSA and CKD is likely to be bi-directional. On one hand, the presence of OSA leads
to intermittent hypoxia, sympathetic nervous system activity, and hypertension, all of which may have
deleterious effects on kidney function. On the other hand, in patients with end-stage renal disease (ESRD),
intensification of renal replacement therapy has been shown to attenuate sleep apnea severity, suggesting
that the renal disease itself contributes to the pathogenesis of OSA. The present review describes our
current understanding of the bi-directional relationship between OSA and CKD.
Recent findings
Studies suggest that the presence of OSA and nocturnal hypoxia may lead to worsening of kidney function.
One potential mechanism is activation of the renin–angiotensin system by OSA, an effect which may be
attenuated by CPAP therapy. In ESRD, fluid overload plays an important role in the pathogenesis of OSA
and fluid removal by ultrafiltration leads to marked improvements in sleep apnea severity.
Summary
OSA is associated with accelerated loss of kidney function. In patients with ESRD, fluid overload plays an
important role in the pathogenesis of OSA.
Keywords
chronic kidney disease, dialysis, end-stage renal disease, fluid overload, obstructive sleep apnea

INTRODUCTION removal by ultrafiltration may attenuate sleep


Obstructive sleep apnea (OSA) is far more common apnea severity.
in patients with chronic kidney disease than in the
general population. The presence of OSA in this
THE IMPACT OF OBSTRUCTIVE SLEEP
population is associated with reduced quality of life,
APNEA ON KIDNEY FUNCTION:
and an increased risk of cardiovascular morbidity
BACKGROUND
and mortality. Compared to the evidence base sup-
porting a relationship between OSA and cardiovas- CKD is defined as a glomerular filtration rate (GFR)
cular disease, research focusing on the relationship less than 60 ml/min/1.73 m2 or pathological evi-
between OSA and CKD is, relatively, in its infancy. dence of kidney damage with a preserved GFR, of
However, a growing body of evidence over the last at least 3 months duration [1]. It has become increas-
15 to 20 years had led to the concept of a bi-direc- ingly common with global prevalence rates of up to
tional relationship between OSA and CKD; that is,
that the presence of OSA may lead to an accelerated a
Department of Medicine, University of Toronto, Toronto, Ontario,
loss of kidney function, and that equally, the pres- Canada, bDepartment of Respiratory Medicine, Far Eastern Memorial
ence of CKD, in particular end-stage renal disease Hospital, New Taipei City, Taiwan, cAP-HP, Groupe Hospitalier Pitié-
(ESRD), contributes to the pathogenesis of OSA. To Salpêtrière Charles Foix, Service des Pathologies du Sommeil, Paris,
France, dDivision of Respirology, Department of Medicine, Women’s
reflect this bi-directional relationship, this review is
College Hospital and eSleep Research Laboratory of the Toronto Reha-
presented in two distinct parts. The first part of the bilitation Institute-UHN, Toronto, Ontario, Canada
review is focused on recent evidence supporting a Correspondence to Owen D. Lyons, MB BCh BAO MRCPI, Department
role for OSA in accelerating decline in kidney func- of Medicine, Women’s College Hospital, 76 Grenville Street, Toronto, ON
tion. In the second part of the review, we consider M5S 1B2, Canada. Tel: +1 416 323 6137; fax: +1 416 323 6132;
the mechanisms by which the presence of ESRD may e-mail: owen.lyons@wchospital.ca
lead to sleep apnea and how intensification of Curr Opin Pulm Med 2018, 24:549–554
renal replacement therapy (RPT) or additional fluid DOI:10.1097/MCP.0000000000000525

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Sleep and respiratory neurobiology

THE IMPACT OF OBSTRUCTIVE SLEEP


KEY POINTS APNEA ON KIDNEY FUNCTION:
 OSA is highly prevalent in patients with CKD. EMERGING EVIDENCE
In a cross-sectional study of 7700 subjects from the
 OSA is associated with accelerated loss of kidney
ESADA cohort, it was shown that, along with recog-
function.
nized traditional risk factors for CKD, the overnight
 Mechanisms by which OSA may lead to an minimum oxygen saturation was also a predictor of
accelerated decline in kidney function include hypoxia, the presence of CKD, with a 2% higher probability of
sympathetic nervous system activation, hypertension, CKD for every unit decrease in the minimum oxy-
and activation of the renin-angiotensin system.
gen saturation [22]. In one prospective study of 858
 In patients with ESRD, fluid overload plays an important patients, unselected for the presence or absence of
role in the pathogenesis of OSA. CKD, who underwent diagnostic sleep testing, GFR
was measured at baseline and then followed over
 Intensification of renal replacement therapy or fluid
removal by ultrafiltration attenuates sleep apnea 2 years [23]. At baseline, GFR was mildly reduced
severity in ESRD. (71  12 ml/min per 1.73 m2), and 44% of patients
had nocturnal hypoxia (oxygen saturation below
90% for 12% of the nocturnal monitoring time).
Over the 2-year period, 5.7% of patients had an
16% [2], largely because of diabetes and hyperten- accelerated decline in GFR (defined as a decline in
sion [3], and is associated with very significant GFR 4 ml/min/1.73 m2 per year). Compared to
morbidity, utilization of healthcare resources, and control patients without hypoxia, patients with
mortality [4,5]. hypoxia had an increased risk of rapid loss of kidney
OSA is a common disorder of repetitive pharyn- function with an odds ratio (OR) of 2.89 (1.25–6.67)
geal collapse during sleep [6]. Although recent studies following adjustment for RDI, age, BMI, diabetes,
have estimated that approximately 10–36% of the and heart failure. In a study of 161 patients with
general population have moderate-severe OSA [7,8], stage 3–4 CKD (mean GFR 31 ml/min per 1.73 m2),
OSA is far more common in CKD populations, with the 4% oxygen desaturation index (4% ODI) and
prevalence rates of over 40% [9–11]. Furthermore, it GFR were measured at baseline [24]. GFR was subse-
has been shown that the prevalence of OSA is further quently measured over one year of follow up.
increased in more advanced stages of CKD [11]. Approximately 10% of patients had moderate-
Although this does not necessarily imply a causal severe oxygen desaturation (4% ODI  15). The
relationship given that both conditions are associ- decline in GFR over 1 year was three to four times
ated with similar comorbidities such as hypertension, greater in patients with 4% ODI at least 15 than
diabetes, and obesity, there is definite biological those with 4% ODI less than 15, after adjustment for
plausibility to support a role for OSA in the patho- baseline characteristic including BMI.
genesis of accelerated decline in kidney function. In contrast to these studies which show a clear
Several key pathological mechanisms are con- association between nocturnal hypoxia and kidney
sidered to play a role in tissue damage in CKD, injury, a recently published substudy from the Wis-
namely chronic hypoxia and glomerular hyperfil- consin sleep cohort study did not show an associa-
tration [12–14]. The kidney, specifically the tion between sleep apnea severity (defined as an
medulla, is particularly sensitive to hypoxia apnea-hypopnea index (AHI) at least 15 or positive
[14,15]. Glomerular hyperfiltration, caused by sys- airway pressure (PAP) use at baseline, and decline in
&&
temic hypertension, leads to glomerular hyperten- kidney function) [25 ]. In this retrospective cohort
sion. Ultimately both pathways may lead to study of 855 patients followed over an average fol-
tubulointerstitial injury, a harbinger of CKD. It is low-up of 13.9 years, the rate of GFR decline
clear that OSA could potentially contribute to both between those with sleep apnea (0.7 ml/min/
of these mechanisms, directly by leading to inter- 1.73 m2/year) and those without sleep apnea
mittent hypoxia [15], and indirectly by causing (0.9 ml/min/1.73 m2/year) was not significantly
hypertension, sympathetic nervous system activa- different. This study was limited by the lack of data
tion, inflammation, oxidative stress, and activation on oxygen saturation during sleep. Furthermore, the
of the renin–angiotensin system (RAS) [16–21]. prevalence of sleep apnea was low at 11%, the
Several studies in recent years, both observational population was relatively young (mean age ¼ 50.4
and interventional, have added to the evidence base years) and healthy with a diagnosis of diabetes
implicating OSA as a pathogenic factor in the wors- mellitus in only 3%, and the mean GFR at baseline
ening of kidney function. was normal (89.3  13.8 ml/minute/1.73 m2). Taken

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Obstructive sleep apnea and chronic kidney disease Lin et al.

together, these issues raise the possibility that this nervous system activation as has previously been
population did not represent an ‘at risk’ group for suggested [33,34].
the development of kidney damage. As such, it may In a post-hoc analysis of the Sleep Apnea Car-
be possible than even longer follow up in this rela- diovascular Endpoints (SAVE) randomized control
tively healthy population would be required to see trial (RCT), the largest study to-date in this field,
an appreciable decline in kidney function. In a study Loffler et al. aimed to assess the effects of CPAP on
of older subjects (age 365 years), recruited from renal function in 200 individuals with coexisting
the general population), of whom 277 patients moderate to severe OSA and cardiovascular disease
&&
underwent overnight polysomnography, there was [35 ]. The mean GFR at baseline was normal and
an increased risk of rapid kidney decline, over an over a median 4.4-year follow up there was no
11-year follow-up, in those with an AHI at least 30 difference in the rate of GFR decline in the CPAP
(OR ¼ 2.80; 95% confidence interval (CI), 1.21– group (1.64, 3.45 to 0.740 ml/min/1.73 m2/yr)
6.44) and the results remained significant after compared to in the usual care group (2.30, 4.53
adjustments for age, sex, BMI, smoking status, dia- to 0.71 ml/min/1.73 m2/yr; P ¼ 0.21) after median
betes mellitus, hypertension, history of cardiovas- follow-up of 4.4 years. Although the results of this
cular disease (OR ¼ 2.50; 95% CI, 1.01–6.20) [26 ].
&&
study do not support the use of CPAP for renal
Several recent short-term studies have focused protection in patients with sleep apnea, the study
on the association between sleep apnea, specifically does provide several insights for design of
nocturnal hypoxia, on the RAS. Zalucky et al. [27], in potential future studies of its kind. The majority
a study of 31 patients with OSA, showed that mod- of patients in the study did not have CKD at base-
erate to severe hypoxia was associated with greater line, patients with severe nocturnal hypoxia were
baseline glomerular pressure (a measure of increased excluded, and based on baseline characteristics,
renal risk), and that severe hypoxia was associated were unlikely to be at high risk for loss of kidney
with greater RAS activity, independent of obesity. function [36]. The design of future studies should
The same group aimed to determine the effect of focus on recruitment of patients ‘at-risk’ for devel-
CPAP on renal hemodynamics and in response to an opment of CKD or indeed those with already
infusion of angiotensin 2, a test which reflects RAS established CKD.
activity [28]. In 20 normotensive patients, predom-
inantly men, mean age of 50, with newly diagnosed
OSA (mean AHI 42  4), it was shown that one THE ROLE OF END-STAGE RENAL
month of treatment with CPAP led to an augmented DISEASE IN THE PATHOGENESIS OF
renal plasma flow response to angiotensin 2, indi- OBSTRUCTIVE SLEEP APNEA:
cating a down regulation of RAS, as well as reducing BACKGROUND
mean arterial pressure, plasma aldosterone, and uri- ESRD represents a stage where kidney function has
nary protein excretion. deteriorated to the point where RPT in the form of a
Several other short-term, nonrandomized stud- transplant or, more commonly, chronic dialysis is
ies, have previously suggested a beneficial effect of required. This is very much an at-risk patient popu-
CPAP on renal hemodynamics in patients with OSA lation with an annual mortality of up to 20%, usu-
[29,30]. However, these results have not been con- ally because of cardiovascular disease [37–39]. Even
sistently seen in other studies. This was reflected in a more so than other stages of CKD, the prevalence of
recent meta-analysis of eight studies (240 individu- sleep apnea is much higher in patients with ESRD
als) that aimed to evaluate the effect of PAP, CPAP, than in the general population, with reported
or adaptive servo-ventilation, on GFR [31]. Overall, prevalence rates as high as 60% [40–42]. Although
there was no change in GFR before and after PAP recognized risk factors for OSA in the general popu-
treatment in patients with sleep apnea. However, lation continue to be of relevance in the pathogen-
albeit in a subgroup analysis, longer duration of esis of OSA in ESRD, the very high prevalence of OSA
usage of PAP treatment and increased age were is not explained solely by increasing age, BMI or
associated with significantly improved GFR follow- comorbid disease, suggesting that the kidney disease
ing PAP therapy [31]. Interestingly, in a prospective, itself contributes to the increased prevalence of OSA
nonrandomized study of the effects of fixed CPAP [43,44]. In support of this are studies showing that
and auto-PAP on kidney function decline in patients intensification of dialysis treatment, in the form of
with OSA, fixed CPAP had an attenuating effect on conversion from conventional hemodialysis (CHD)
the rate of kidney function decline whereas auto- to nocturnal hemodialysis (NHD), or from continu-
PAP did not [32], with the authors postulating that ous ambulatory peritoneal dialysis to nocturnal
CPAP may have had a more significant beneficial peritoneal dialysis, attenuates sleep apnea severity
effect on blood pressure control and sympathetic in patients with ESRD [45,46].

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Sleep and respiratory neurobiology

Both upper airway occlusion and destabilization and legs were also greater (P < 0.05) in those with
of central ventilatory control may lead to OSA. In sleep apnea than in those without. Although there
ESRD, enhanced ventilatory sensitivity to hypercap- was a higher proportion of males and older patients
nia has been shown to correlate with apnea severity in the sleep apnea group compared to the no sleep
[47]. Furthermore, a reduction in ventilatory sensi- apnea group, there was no difference in BMI
tivity following conversion from CHD to NHD was between the groups. Furthermore, in a multivariate
associated with a reduction in the severity of OSA analysis, the total body extracellular fluid volume
[48]. A role for fluid overload and rostral fluid shift was the only factor that was independently and
in the pathogenesis of sleep apnea has been shown directly related to sleep apnea severity, as measured
by the AHI (r ¼ 0.47; P ¼ 0.002) [55 ].
&&
in various different patient populations [49], with
the most striking data coming from conditions Similarly, a recent prospective study conducted
characterized by fluid overload such as heart failure of 55 patients with ESRD on conventional HD dem-
and ESRD [50–52]. In brief, fluid accumulation in onstrated that an inter-dialytic weight gain more
the legs during the day redistributes rostrally upon than 2 kg was more frequent in patients with OSA
than in those without (96 vs. 53%; P ¼ 0.002) [56 ].
&
lying down at night. The degree of this fluid shift is
of a greater magnitude in patients with fluid over- Increased interdialytic weight gain more than 2 kg
load compared to those without. Subsequent fluid and the left ventricular diastolic diameter were inde-
accumulation in the neck may lead to a reduction in pendently associated with OSA. Furthermore, over a
upper airway cross-sectional area and increased col- median follow up of 45 months, OSA was found to
lapsibility predisposing to OSA, whereas fluid accu- be associated with as significantly higher risk of
&
mulation in the lungs may stimulate pulmonary cardiovascular events [56 ]. In a study of seventeen
irritant receptor, leading to a cycle of hyperventila- patients with ESRD with moderate–severe OSA on
tion and apnea, and predisposing to central sleep CHD, Ogna et al. [57] demonstrated, using bioelec-
apnea (CSA) [52,53]. trical impedance to measure fluid volumes, that the
degree of fluid overload post hemodialysis was the
best predictor of sleep apnea severity. Taken
THE ROLE OF END-STAGE RENAL together, and allowing for the inherent limitations
DISEASE IN THE PATHOGENESIS OF of observational studies, these studies provide fur-
OBSTRUCTIVE SLEEP APNEA: EMERGING ther evidence to support the concept that fluid
EVIDENCE overload is an important factor in the pathogenesis
Recently, Tanaka et al. aimed to identify predictors of sleep apnea in CKD and ESRD.
of sleep apnea in a cross-sectional study of patients Previously, it has been shown that following
with CKD with a GFR less than 60 ml/min/1.7 m2, conversion from nocturnal peritoneal dialysis to
&
who were not on dialysis [54 ]. Similar to previous continuous ambulatory peritoneal dialysis there
studies in patients with CKD/ESRD, there was a high was an increase in sleep apnea severity accompanied
prevalence of sleep apnea with 39% of the cohort by reduced pharyngeal volumes and cross-sectional
having severe OSA, despite a relatively low mean area and enlargement of the tongue measured by
BMI of 24  3.9 kg/m2. Significant differences in volumetric MRI [58]. Uremic clearance also wors-
brain natriuretic peptide (BNP) level (213.6  ened. However, similar to other studies showing
329.6 pg/ml vs. 107.8  141.3 pg/mL; P < 0.05) intensification of dialysis attenuates sleep apnea
and cardiothoracic ratio (CTR, 52.4%  6.3% vs. severity [45], it is not possible to elucidate the degree
49.6%  5.7%; P < 0.05) were seen between patients to which changes in fluid volume control or changes
with and without severe OSA. Following adjustment in metabolic status led to a change in sleep apnea
for confounders, sleep apnea severity was indepen- severity in these studies. To this end, it was demon-
dently associated with various markers of fluid over- strated, in a recent study of 15 patients with sleep
load, including BNP levels, cardio-thoracic ratio apnea, including OSA and CSA, that removal of 2.2 l
calculated from chest radiograph, and diameter of of fluid during a single ultrafiltration session led to a
the inferior vena cava (all P < 0.005) rather than 36% reduction in AHI, in the absence of any changes
&
cardiac systolic or diastolic function [54 ]. in uremic or metabolic status [59]. Furthermore, the
In a study of in 42 patients with ESRD on thrice- degree of reduction in AHI correlated with the
weekly CHD, Lyons et al. showed that total body degree of reduction in total body extra-cellular fluid
extracellular fluid volume, measured by bioelectri- volume (r2 ¼ 0.322; P ¼ 0.027). Interestingly, the
cal impedance, was 2.6 l greater in those patients reduction in fluids volumes was accompanied by
with moderate-severe sleep apnea (n ¼ 28) compared an increase in transcutaneous PaCO2 into the nor-
to those with mild or no sleep apnea (n ¼ 14; mal range, suggesting potentially a reduction in
P ¼ 0.006) [55 ]. Fluid volumes in the neck, thorax,
&&
respiratory drive and possibly an increase in

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Obstructive sleep apnea and chronic kidney disease Lin et al.

ventilatory stability [59]. A marked improvement in yet, unclear role played by uremia on sleep apnea
sleep quality was also seen following fluid removal severity, would allow for a potentially more
by ultrafiltration. These findings support a key role nuanced approach to modifying dialysis/ultrafiltra-
for fluid overload in the pathogenesis of sleep apnea tion regimes to attenuate sleep apnea severity.
in ESRD, and demonstrate that fluid removal by
ultrafiltration attenuates sleep apnea without alter- Acknowledgements
ing uremic status. None.
Previously, it has been shown, in OSA patients
without renal disease that the use of compression
Financial support and sponsorship
stocking during the day attenuates sleep apnea
severity by prevention of fluid accumulation in None.
the legs during the day, and its nocturnal displace-
ment into the neck [60,61]. Following from this, a Conflicts of interest
recent study aimed to assess the role of compression The authors declare no conflict of interest.
stockings in ESRD patients with OSA [62]. Although
there was a statistically significant reduction in AHI
with the use of compression stockings over a 1-week REFERENCES AND RECOMMENDED
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