J Am Soc Nephrol 12: 28542859, 2001

DISEASE OF THE MONTH

Eberhard Ritz, Feature Editor

Sleep Apnea in Renal Patients

CARMINE ZOCCALI, FRANCESCA MALLAMACI, and GIOVANNI TRIPEPI
CNR Centro Fisiologia Clinica, Reggio Calabria, Italy.

In Western societies, sleep apnea (SA) has emerged as a

major medical problem with important social (1) and financial
implications. The issue may be even more relevant in nephrology because some of the factors involved in the pathogenesis
of renal disease are the same that cause, or are associated with,
SA in the general population. The interest in this syndrome is
continuously increasing in the renal community, but many
nephrologists do not fully appreciate its potential clinical implications. Before reviewing in some detail the particular situation of SA in chronic renal diseases, we therefore briefly
review definitions, general pathophysiology, and types of SA
first (2).

Definitions and Pathomechanisms

SA is defined as an intermittent interruption of airflow at the
level of nose and mouth during sleep. Episodes of apnea are
considered important if they persist for longer than 10 s, but in
some cases they may last as long as 2 min. The SA syndrome
is the clinical consequence of frequent episodes of apnea
during sleep. Usually patients with the full-blown syndrome
have at least ten episodes of apnea per h. The syndrome is
probably the most important cause of daytime somnolence. Its
prevalence is at least 2% in middle-age women and 4% in
middle-aged men. The following types of apnea can be distinguished: (1) obstructive, (2) central (i.e. neurally mediated),
and (3) mixed. Obstructive SA (OSA) is characterized by a
cessation of airflow caused by occlusion of the oropharyngeal
tract and central SA (CSA) by a transient abolition of the
neural drive to respiratory muscles. Mixed apnea represents a
combination of the two forms.

Obstructive Sleep Apnea

OSA typically occurs in males in an age range between 30
and 60 y and is characterized by a history of snoring, excessive
daytime sleepiness, noctural choking or gasping, and moderate
obesity.
The underlying disturbance in OSA is transient airway occlusion, usually at the level of the oropharynx. The airway

Received March 1, 2001. Accepted March 10, 2001.

Correspondence to Dr. Carmine Zoccali, CNR Centro Fisiologia Clinica, Via
Sbarre inferiori 39, I-Reggio Calabria 89131, Italy. Phone: 0039-0965-397010;
Fax: 0039-0965-56005; E-mail: czoccali@diel.it
1046-6673/1211-2854
Journal of the American Society of Nephrology
Copyright 2001 by the American Society of Nephrology

occlusion provokes progressive asphyxia, which in turn elicits

a brief arousal reaction restoring airway patency. This phenomenon occurs in a cyclic fashion, sometimes up to 500 times per
night, and causes sleep fragmentation. The airway collapse in
OSA depends on the inability of the airway dilator and abductor muscles to maintain airway patency during inspiration, i.e.
when subatmospheric pressure is generated inside the respiratory system. By reducing muscular tone of the upper airways,
sleep has a permissive role on airway collapse. Alcohol may be
an important contributory factor. Structural abnormalities, such
as macroglossia, retrognathia, and adenotonsillar hypertrophy,
may generate as well as aggravate OSA. By increasing the fat
content of the pharynx, obesity is another frequent condition
contributing to OSA. Snoring, i.e. high frequency vibration of
the palatal and pharyngeal soft tissues that results from the
reduced size of the upper airway lumen, may further exacerbate the process by inducing soft tissue edema. Snoring usually
precedes by several years the development of full-blown OSA,
but only a minority of snoring patients have OSA. Recurrent
episodes of nocturnal hypoxemia and arousal eventually lead to
the full-blown OSA syndrome, which is characterized by additional neuropsychiatric and behavioral disturbances. These
include excessive and progressive daytime sleepiness which
often reaches a disabling degree as well as memory and personality disturbances. In men, impotence is a relatively frequent complaint.
OSA induces also important cardiorespiratory complications, which are considered a consequence of the recurrent
episodes of nocturnal hypoxemia. Cyclical bradycardia during
the apneic episodes, followed by tachycardia during the ensuing ventilatory phases, is frequently found. In a minority of
cases, bradycardia may end up in prolonged asystolic periods
or in various forms of tachyarrhythmia, including ventricular
tachycardia. Arrhythmias in OSA may cause sudden death
during sleep. Arterial pressure rises abruptly at the termination
of each obstructive event. OSA is typically associated with
nocturnal hypertension and with an inverted 24-h arterial pressure profile. OSA is a recognized risk factor for systemic
hypertension (3,4) and perhaps also for myocardial infarction,
stroke, and death (57). It is important to bear in mind that
obstructive SA may precipitate left ventricular failure in patients with heart disease. Increased afterload during obstructive
events, nocturnal hypoxemia, and the ensuing elevated sympathoadrenal activity all conjure to impair left ventricular function (8). On the other hand, a minority of patients with severe
OSA, usually obese patients with sustained daytime hypox-

J Am Soc Nephrol 12: 28542859, 2001

Sleep Apnea in Renal Patients

emia, develops frank pulmonary hypertension, right ventricular

failure, polycythemia, and chronic hypercapnia and hypoxemia. Upper airway collapse may also induce central sleep
apnea by eliciting reflexes that inhibit the respiratory drive.
The cardiovascular consequences of OSA will be discussed
further in the paragraph dealing with renal diseases.

Central Sleep Apnea

In contrast to OSA, the apneic events in CSA are associated
with a decreased or absent ventilatory effort. CSA depends on
a defective central drive to the ventilatory muscles. The resulting apnea has pathophysiologic consequences that are similar
to those of OSA.
Normally, the rate and depth of breathing are regulated by a
negative feedback system that maintains the partial pressure of
arterial CO2 (pCO2) within a narrow range. Changes in pCO2
lead to changes in ventilation: the greater the sensitivity to
CO2, the greater the ventilatory response. Among normal persons, there is considerable variation in the sensitivity to CO2,
which may in part be related to genetic influences. Diminished
sensitivity to CO2 increases the risk of chronic hypercapnia in
patients with established pulmonary disease. Conversely, an
increase in CO2 sensitivity minimizes perturbations in the
partial pressure of arterial CO2. In theory, this should offer
protection against the long-term sequelae of hypercapnia in
patients with cardiopulmonary disease. Although this protective mechanism is advantageous during waking hours, the
increased sensitivity may destabilize breathing during sleep
when ventilation decreases and the partial pressure of CO2
rises (approximately 5 mmHg). In persons with increased
sensitivity to CO2, the negative feedback system that controls
breathing elicits a large ventilatory response when the pCO2
rises; the consequent hyperventilation, by driving the pCO2
below a certain level (the apneic threshold) then results in

central apnea. As a consequence of apnea, the pCO2 rises

again, which leads to an increase in ventilation. In this fashion,
cycles of central apnea and hyperventilation recur during sleep
(Cheyne-Stokes respiration). Patients with hyperventilation
(driven by cardiopulmonary disease, metabolic acidosis, fever,
and other causes) often develop CSA because during the awake
state hyperventilation reduces pCO2 below the critical value,
which elicits CSA. Heart failure (see below) is frequently
associated with CSA (8). Primary hypoventilatory syndromes
that are caused by altered metabolic control of respiration or
disease of respiratory muscles are a rare cause of CSA.

Diagnosis
The diagnostic criterion standard for SA and for differentiating OSA from CSA is polysomnography, i.e. an overnight
sleep study that includes (1) neurophysiologic variables (EEG,
electrooculogram, and submental myogram) that allow a clear
identification of sleep stages, (2) measurements of respiratory
effort (respiratory inductive plethysmography or esophageal
pressure measurements) that are aimed at detecting and classifying apnea as of central (CSA) or obstructive (OSA) origin,
(3) arterial O2 saturation by pulse oxymetry, (4) heart rate, and
(5) transcutaneous pCO2.
The main informations derived from polysomnography are
schematically summarized in Table 1. The diagnosis of OSA is
established when episodes of airflow cessation at the nose and
mouth (at least ten episodes of apnea per h) are documented
despite simultaneous evidence of continuing respiratory effort.
Because of the cost of polysomnography, there is considerable
interest in simplified, unattended, ambulatory sleep monitoring
for home studies. The most useful test is the recording of
arterial O2 saturation by oxymetry. The reliability of overnight
oxymetry in the diagnosis of OSA depends on the pretest
probability of the disorder. In patients with a high pretest

Table 1. Main information derived from polysomnography (also see text)a

Total sleep time
Arousal
Apnea
obstructive
central
mixed
Hypopnea

Apnea index
Apnea-hypopnea index

Oxygen saturation
Periodic limb movements
Body position
a

Light (1 and 2) and deep (3 and 4) sleep stages and REM sleep
Full awakening or 3 s EEG shift to a lighter sleep stage. The arousal index is the
ratio of the number of arousals to total sleep time (h)
Total absence of airflow for 10 s or longer
An event with evidence of respiratory effort
An event with absence of respiratory effort
An event with initial absence of respiratory effort followed by a respiratory effort
A decrease 50% in the amplitude of breaths lasting 10 s or a clear decrease
in amplitude of breaths (50%) associated with an arousal or a decrease in O2
saturation 3%
Ratio of the number of episodes of apnea to total sleep time (h)
Ratio of the number of episodes of apnea hypopnea to total sleep time (h).
Different authors gave different definitions of the normal limit, ranging from 5
to 15/h
Number of episodes of O2 desaturation (a decrease 4%); mean O2 saturation;
nadir of O2 saturation; average O2 desaturation
Either as isolated events or associated with arousals
Dependence on apneic events

REM, rapid eye movement; EEG, electroencephalogram.

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Journal of the American Society of Nephrology

probability (based on clinical symptoms and witnessed episodes of apnea during sleep), overnight oxymetry is of proven
usefulness to confirm the diagnosis by documenting episodes
of arterial O2 desaturation (at least ten episodes per h). However, negative results in those with a high clinical probability
do not exclude the diagnosis, and polysomnography in these
cases is mandatory to exclude OSA. When the pretest probability of OSA is low (in the occasional snorer with rare episodes of daytime disturbance), the absence of arterial O2
saturation virtually excludes the diagnosis, rendering polysomnography unnecessary.
The key element for the diagnosis of CSA is the documentation of recurrent episodes of apnea (at least five per h) that
are not accompanied by respiratory effort.

Relation of Sleep Apnea to Hypertension, Heart

Failure, and Renal Disease
SA alters several mechanisms that regulate extracellular
fluid volume and vascular tone. It is apparently also related to
systemic hypertension. Furthermore, SA can be a complication
of advanced renal insufficiency. As alluded to above, SA may
be of particular relevance in heart failure because it aggravates
ventricular afterload by direct and indirect mechanisms. Recognizing the link between SA and cardiorenal physiology is
important because it has implications for the prognosis and the
treatment of patients with primary and secondary forms of the
syndrome.

Body Fluid Homeostasis

By profoundly altering cardiopulmonary dynamics, SA induces reflex circulatory responses that critically affect renal
function and body fluid volume homeostasis. Nocturnal secretion of atrial natriuretic peptide (ANP) is increased and renin
secretion decreased, suggesting increased cardiac preload as in
a state of hypervolemia (19). When patients are awake, however, hypervolemia is not demonstrable, indicating that apneic
episodes promote a volume shift from the peripheral to the
central circulation, i.e. central hypervolemia.

Hypertension and Heart Failure

There are important links between OSA or CSA and hypertension or heart failure, respectively. OSA is associated with
hypertension and CSA with heart failure. These two conditions
are challenging problems in patients with end-stage renal
disease.
It is well documented that BP rises in a very consistent
fashion during apneic episodes. The mechanisms responsible
for this phenomenon are complex because the direct effects of
apnea (hypoxemia and low intrathoracic pressure) are modified
by cardiopulmonary reflexes. Undoubtedly, the rapid increase
in arterial pressure that occurs at the end of an apneic episode
is mainly mediated by surges in sympathetic function during
the arousal reaction. Whether periodic nocturnal hypoexmia
induces sustained hypertension during daytime as well is somewhat controversial. The problem has considerable epidemio-

J Am Soc Nephrol 12: 28542859, 2001

logic relevance given the high frequency of OSA in the adult

population.
To clarify the relationship between OSA and hypertension, it
is necessary to address the following issues. What is the nature
of this relationship; is the risk of hypertension in patients with
OSA truly independent of other risk factors? Is it possible to
reverse hypertension by specifically treating SA with continuous positive airway pressure (CPAP)? As to the first question,
age, gender, body mass index, and alcohol as well as tobacco
consumption are major confounders of the relationship between SA and BP. In some studies, the link was markedly
attenuated when these factors were appropriately accounted for
(9). Furthermore, in some early studies, the techniques applied
to diagnose SA, to measure arterial pressure, and to characterize patients were not adequate. Recent large-scale surveys and
cohort studies have produced a convincing answer that is based
on solid scientific evidence. The Wisconsin Sleep Cohort
Study (3) included 709 individuals of both sexes and was based
on polysomnography and well-standardized arterial pressure
measurements. This study showed that there was a dose response relationship between sleep-disordered breathing at
baseline and BP at follow-up. Importantly, this response was
independent of known confounding factors such as obesity and
alcohol and tobacco consumption. The contribution of SA to
hypertension in this cohort was weak (odds ratios for hypertension at the 4-y follow-up: 1.4 [no apneic events] to 2.9 [15
episodes of hypopnea or apnea per h]). Similar observations
were reported in a large cross-sectional analysis of 6132 subjects enrolled in the Sleep Heart Study (4). In cross-sectional
studies that are designed to investigate whether SA is related to
increased mortality, bias will lead to underestimation of the
true relative risk of hypertension because survival of subjects
with disordered breathing during sleep is less (prevalence/
incidence bias).
As to the second question there is little doubt that CPAP
virtually eradicates cyclic BP surges. However, the chronic
effects of CPAP on daytime hypertension remain uncertain
because most studies addressing this problem suffer from the
methodological flaws discussed above. Further shortcomings
are low compliance and/or short follow-up. A recent study by
Dimsdale et al. (10) examined the BP effect of CPAP treatment
for 1 wk in 39 patients with obstructive SA. The strength of
this study is that it is the only one that includes a placebo arm,
i.e. CPAP administered at an ineffective pressure. Nighttime
mean arterial pressure levels decreased to a much greater
extent over time in the patients who received active CPAP
treatment. However, the daytime decrease was not significantly
greater in the active treatment group than in the placebo group,
suggesting that the response was in part nonspecific. The very
short treatment period and the tendency for BP to decrease
toward the end of the active treatment period are obvious
limitations of this study. There is obviously a need for properly
designed investigations to estimate the true effects of CPEP on
arterial pressure. Despite the methodological difficulties encountered in this area, there is agreement that hypertensive
patients with apneic episodes are a highly heterogenous population. Some of them retain normal nocturnal BP dipping, and

J Am Soc Nephrol 12: 28542859, 2001

others develop frank nocturnal hypertension. These nondippers

may be at higher cardiovascular risk.
At variance with systemic hypertension, which is typically
associated with OSA, patients with heart failure display a high
prevalence of CSA (up to 40%). Low cardiac output causes
respiratory instability because it prolongs the time lag between
changes in blood chemistry induced by ventilation (pO2, pCO2,
and pH) on the one hand and detection of these changes by the
chemoreceptors on the other hand. Consequently, the ventilatory drive remains inappropriately high because pCO2 in the
central nervous system lags behind pCO2 in the circulation.
When pCO2 is reduced below the apneic threshold, respiration
ceases. It starts again as CO2 accumulates in blood, thus
generating periodic breathing. Individual sensitivity to CO2
plays an important role in precipitating CSA in patients with
heart failure because CSA episodes are far more common in
patients with relatively low CO2 sensitivity (11). As mentioned
above, patients with OSA may develop heart failure because of
the detrimental effects of episodes of obstructive apnea on
myocardial performance. In these cases, CPAP, by alleviating
OSA, reduces left ventricular afterload and improves arterial
oxygenation during sleep. On this basis, CPAP has been proposed as a non-pharmacologic adjunct for reducing afterload
during nighttime in patients who are on pharmacologic treatment for heart failure. When heart failure is associated with
CSA, theophylline reduces the number of apneic episodes (12)
and may represent an alternative, or complementary, approach
to the administration of nasal oxygen.

Sleep Apnea in End-Stage Renal Disease (ESRD)

Disturbed sleep is common in uremia. Up to 80% of chronic
dialysis patients complain of sleep disturbances and reduced
daytime alertness. Sleep disruption is a problem of paramount
importance that is still inadequately appreciated by nephrologists. In healthy young subjects, restricting time in bed to 4 h
per night for 6 d induces striking alterations in metabolic and
endocrine function, including increased sympathetic tone and a
state of insulin resistance (13). Both abnormalities are well
known complications of chronic uremia. There are only a few
valid studies, i.e. based on electrophysiologic recordings in the
sleep laboratory, which documented the occurrence of sleep
apnea in dialysis patients (14 23). Furthermore, these studies
were performed in patients who complained of sleeping problems and are therefore not indicative of the true prevalence of
this disturbance in the dialysis population. The reported prevalence rate in selected cases ranged from 53 to 75%. A very
recent estimate suggests that the overall prevalence may be
about 15% (21). Because sleep apnea is common in ESRD, the
nephrologist ought to have a high degree of suspicion in
patients complaining of the symptoms and/or presenting the
signs indicated in Table 2.
The high frequency of SA in renal failure is in part explained
by the fact that the most common comorbid conditions of
ESRD, namely atherosclerosis and diabetes, are also independently associated with this syndrome. Although apnea in the
general population is mostly of the obstructive type, the obstructive (OSA) and the central (CSA) types are almost equally

Sleep Apnea in Renal Patients

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Table 2. Symptoms and signs that point to sleep apnea

Male gender, older age, and family history
Excessive daytime sleepiness in situations demanding
alertness. A history of motor vehicle accident or near miss
associated with sleepiness
High alcohol intake or use of sedatives
Anatomic abnormalities in the airways (macroglossia, short
mandible, adenotonsillar hypertrophy) or large neck size
(43 cm)
Obesity (body mass index 30 kg/m2)
Habitual snoring
Witnessed apnea or gasping for breath during sleep
A high index of suspicion is appropriate in patients
presenting with severe hypertension

frequent in patients with ESRD. Uremic patients with preexistent heart failure are likely to present a predominantly central
SA pattern. Despite the confounding effect of preexistent cardiovascular disease, there is little doubt that uremia per se is
associated with SA and that this disturbance plays a major role
in disrupting sleep in dialysis patients. Sporadic observations
that SA is at least partly reversible after renal transplantation is
convincing proof that SA is a direct consequence of renal
failure (22,23).
The factors responsible for SA in ESRD are unclear.
Chronic metabolic acidosis impinges on an important stimulus
for respiration by inducing a compensatory fall in pCO2. However, in the seminar study by Kimmel et al. (16) no relationship
was found between metabolic acidosis and apneic episodes in
dialysis patients. The pCO2 level below which the breathing
stimulus ceases, i.e. the apneic threshold, increases during
sleep. It has been suggested that this threshold is increased in
chronic uremia, which would increase the risk of CSA. To our
knowledge, pCO2 measurements during sleep have not been
reported in chronic renal failure. Anemia is another hypothetical factor, but an unpublished observation by Benz et al. (24)
shows that correction of anemia has no effect on sleep apnea.
The hypothesis has been advanced that accumulation of endogenous substances, e.g. endogenous opiods (25,26) destabilize breathing, but supportive data have not been provided.
Central uremic neuropathy may in theory reduce airway muscle tone during sleep or destabilize respiratory control, but
again the issue remains a matter of speculation. The level of
several cytokines, which may influence sleep, is elevated in
dialysis patients (27).
As discussed above sleep apnea impinges heavily on the
quality of life by disrupting the sleep. Another important
reason why it should not be overlooked by the nephrologist is
its association with various cardiovascular complications,
ranging from cardiac ischemia, left ventricular hypertrophy,
heart failure, and arrhythmia to cardiorespiratory arrest (9 13).
It is reasonable to assume that SA contributes to cardiovascular
morbidity and mortality in these patients, but until now no
solid evidence has been provided in support of this hypothesis.
In a recent retrospective study in a group of dialysis patients

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with sleep problems, periodic limb movements rather than

sleep apnea predicted death (28). However, the interpretation
of this intriguing study is difficult because of the small number
of patients, the fact that they were selected, and the failure to
control for confounding factors. The issue is a crucial one
because SA may be a target for intervention.
Long-term sequelae of sleep apnea may be caused by direct
sympathetic activation secondary to chemoreceptor stimulation
by episodic hypoxemia and hypercapnia and stress from
chronic disruption of sleep. Hypoxemia is dangerous, and
increased sympathetic activity is a counter-regulatory response
that is aimed at preserving organ oxygen supply by increasing
cardiac output, modifying blood flow distribution, and improving delivery of O2 to the tissues. Intermittent hypoxia causes
sympathetic activation that outlasts the triggering stimulus
(29). Fletcher et al. (30) observed that norepinephrine and
epinephrine excretion is high in patients with SA, and this was
true not only during nighttime but also during daytime. In the
general population, the role of sympathetic overactivity as a
cardiovascular risk factor involved in the genesis of hypertension and cardiac hypertrophy is well established (31). Increased sympathetic activity presumably explains the association of SA with insulin resistance (27,32), which is also
frequent in chronic uremia. Endothelial cells are another target
of SA because hypoxia triggers the production of endothelin 1,
a long-lasting vasoconstrictor, which may induce cardiac and
vascular hypertrophy (33) and impair the synthesis of NO, a
vasodilator and antiproliferative compound (34). Endotheliumdependent vascular relaxation is defective in hypertensive patients with obstructive sleep disorder, and this defect is largely
independent of hypertension (34). The link between obstructive SA and endothelial distress may in part explain the endothelial cell dysfunction in ESRD.
The evidence that SA induces cardiovascular complications
in ESRD is circumstantial. It has been shown that nocturnal
hypoxemia is associated with nocturnal hypertension in dialysis patients (35). It is even more strongly associated with
cardiac remodeling in concentric hypertrophy (36). SA is commonly associated with disturbed autonomic control of the
cardiovascular system (37), and this holds true also in dialysis
patients as well (38). Observational and interventional studies
are sorely needed to test the hypothesis that SA and the
attendant nocturnal hypoxemia are causally related to the high
cardiovascular risk in dialysis patients.
Although the formal diagnosis of SA requires polysomnographic studies, nocturnal pulse oximetry at home is a good
screening procedure in patients with ESRD because of the high
pretest probability of SA. A positive test most likely indicates
the presence of true SA, but a negative test has relatively low
negative prediction power (39). Nocturnal hypoxemia by ambulatory pulse oxymetry is correlated with several biologic and
socioeconomic parameters in ESRD patients (40). Reliable
home techniques for the diagnosis (4) and screening (41) of SA
are now emerging. Hopefully, these simpler and cheaper methods will allow appropriate diagnosis in many patients in whom
it would otherwise remain undetected and untreated.
The treatment of SA depends on whether one deals with

J Am Soc Nephrol 12: 28542859, 2001

OSA or CSA. The treatment of OSA should address the underlying pathophysiology. In obese patients, the patency of
airways may be improved by weight reduction if appropriate
oral or nasal prostheses should be provided. Avoidance of
alcohol and sedatives may produce substantial improvement.
Protriptyline is useful in mild to moderate SA, but it has
marked side effects that range from excessive sedation to
orthostatic hypotension. There is practically no controlled experience in uremic patients with OSA. In moderate to severe
OSA, uvulopalatopharnygoplasty (resection of redundant soft
tissue) and nasal CPAP during sleep are therapeutic options.
Uvulopalatopharyngoplasty increases the pharyngeal lumen.
Long-term benefit is reported in about half of the cases, but
evidence on the efficacy of this surgical approach in ESRD
patients is not available. Nasal CPAP keeps the pharyngeal
airway open by delivering positive pressure through a nasal
mask. It is undoubtedly the most efficacious approach. SA is
relieved in about three quarters of the patients. CPAP has been
tested in dialysis patients and proved to be beneficial (20). The
effect of kidney transplantation on SA has been studied in only
three dialysis patients and was curative in all (22,23).
Hypoxemic patients with CSA usually respond favorably to
nocturnal supplemental oxygen. CPAP is efficacious not only
in OSA, but also in CSA. Perhaps the small increase in pCO2
elicited by the added expiratory mechanical load in part explains the beneficial effect of this treatment in OSA. As discussed by Jahaveri et al. (8), CPAP and theophylline are valid
options if CSA is secondary to congestive heart failure.

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