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NDT Advance Access originally published online on October 5, 2006
Nephrology Dialysis Transplantation 2007 22(1):28-31; doi:10.1093/ndt/gfl582
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Sleep apnoea in end-stage renal disease: a short review of mechanisms and potential benefit from its treatment

Indranil Chakravorty1, Manu Shastry2 and Ken Farrington3

1Department of Respiratory Medicine, 2Medicine and 3Department of Renal Medicine, East & North Herts NHS Trust, Lister Hospital, Stevenage, Herts, UK

Correspondence and offprint requests to: Dr I. Chakravorty, Department of Respiratory Medicine (L118), East & North Herts NHS Trust, Lister Hospital, Coreys Mill Lane, Stevenage, Herts SG1 4AB, UK. Email: Indranil.chakravorty{at}nhs.net

Keywords: atrial natriuretic peptide; brain natriuretic peptide; chronic heart failure; continuous positive airway pressure; end-stage renal disease; sleep apnoea



   Introduction
Top
 Introduction
Sleep apnoea
 Sleep studies
 Treatment options
 Homoeostasis in SA
 SA in end-stage renal...
 Potential benefits from...
 References
 
Patients with end-stage renal disease (ESRD), even with adequate renal replacement therapy have a high mortality, primarily from cardiovascular causes, often including heart failure [1]. Sleep studies in ESRD patients have identified increased prevalence of sleep apnoea (SA), both obstructive and central in origin [2]. The presence of untreated SA may further impair fluid balance, cardiovascular function and increase mortality through abnormal vagal or sympathomimetic responses and hypoxia [3].

The availability of brain and atrial natriuretic peptides (BNP/ANP) assessments has opened up possibilities for identifying patients with impaired fluid balance and cardiovascular function [4], who may be at greater risk. The availability of simple and relatively inexpensive [5] treatment options for SA such as continuous positive airways pressure devices (CPAP) [6] may improve survival in these patients, if diagnosed and treated appropriately [7].



   Sleep apnoea
Top
 Introduction
 Sleep apnoea
Sleep studies
 Treatment options
 Homoeostasis in SA
 SA in end-stage renal...
 Potential benefits from...
 References
 
SA may be obstructive or central. Obstructive sleep apnoea (OSA) is characterized by a complete or partial obstruction of the upper airways, due to relaxation of the musculature combined with mechanical factors, such as tissue adiposity and cranio-facial structure, which causes apnoea or hypopnoea during sleep [8]. Central apnoea (CSA) on the other hand is due to a cessation of voluntary respiratory drive from the central respiratory centre in the hypothalamus [9]. The airway remains open during CSAs/hypopnoeas. These apnoeas and hypopnoeas are often accompanied by arterial hypoxia [8], a rise in carbon dioxide and increased sympathomimetic discharge. The net result is a repetitive interruption of nocturnal sleep [8], increased heart rate, reversal of the diurnal variation of blood pressure and daytime fatigue and hypersomnolence [8]. There are complex relationships between SA and increased cardiovascular risks [10]. Patients are at increased risk of developing essential hypertension [10], heart disease and mortality due to cardiovascular causes [11]. There is an increased risk of ischaemic stroke in patients with untreated SA and direct consequences on recent memory retention, reduced neuro-psychological function [12], depression and deteriorating quality of life [12].

The definition of the OSA syndrome [8] includes a combination of snoring and daytime sleepiness combined with a demonstration of at least five nocturnal apnoeas or hypopnoeas per hour during sleep. An apnoeic episode is a complete cessation of breathing for a period of 10 s. Hypopoea is reduction of the tidal volume to <50% of normal for a period of 10 s. The severity is measured by the number of apnoeic/hypopnoeic episodes per hour (also known as Apnoea Hypopnoea Index–AHI)

Obstruction results from the collapse of the upper airway due to relaxation of muscle tone during sleep. Subjects with anatomically narrow airways, small mandible (micrognathia)/posterior positioned mandible (retrognathia), central obesity (with deposition of excess submucosal tissue in the oropharynx) are predisposed to have OSA. These people require increasing activity of the pharyngeal dilator muscles to maintain airway patency.

Apnoea results in a drop in arterial oxygen saturation and a rise in carbon dioxide tension. The stimuli from chemoreceptor and the pharyngeal pressure receptors is postulated to cause arousals from sleep, which can be measured as phase changes in electroencephalographic monitoring of sleep staging [8]. Patients with upper airway resistance (UAR) syndrome also have arousals due to increased work of breathing in the absence of apnoeas or hypopnoeas [8]. Frequent arousals from sleep whether it be due to obstructive apnoeas, hypopnoeas, CSAs or UAR lead to the fragmentation of sleep and arousals, which can be up to a hundred times a minute. A high index of suspicion is necessary to consider investigation using sleep studies.



   Sleep studies
Top
 Introduction
 Sleep apnoea
 Sleep studies
Treatment options
 Homoeostasis in SA
 SA in end-stage renal...
 Potential benefits from...
 References
 
These include:

  1. Overnight oximetry which has high specificity but very low sensitivity in detecting apnoeas resulting in arterial oxygen desaturations. An episode involving a 4% or greater decline in arterial saturation from baseline for 10 s is counted and an index greater than 15/h is considered significant [8].
  2. A limited sleep study (respiratory polygraphy): in addition to oximetry this includes monitoring other channels like snoring, body movements, chest and abdominal wall movements, heart rate and oro-nasal airflow.
  3. Full polysomnography: this includes EEG, EOG and EMG recording in addition [8].



   Treatment options
Top
 Introduction
 Sleep apnoea
 Sleep studies
 Treatment options
Homoeostasis in SA
 SA in end-stage renal...
 Potential benefits from...
 References
 
Although life style changes, alteration of sleep hygiene parameters and reduction of obesity have a significant role in reducing overall disease severity and associated vascular risks, these strategies are often difficult to offer and monitor in traditional health care delivery terms [13]. Management of obesity involving surgical approach is the only proven effective way, but often with increased morbidity.

CPAP involves delivering compressed air with a mechanical device to the patient via a nasal or face mask. This mechanically prevents the collapse of the airways accompanying the sleep related pharyngeal muscular hypotonia [14]. CPAP has been shown to abolish nocturnal apnoeas and hypopnoeas, improve daytime somnolence, performance, neuro-psychiatric state [12], quality of life and reduce blood pressure in OSA patients [14].

Mandibular advancement splints (MAS) are effective in increasing the oro-pharyngeal airway diameter, move the base of the tongue forward, and have been shown to be a useful alternative in mild to moderate cases [15]. Surgical procedures which include palatoplasty, uvulopalatoplasty, tonsillectomy and adenoidectomy and maxillo facio surgery are useful in patients (often children) with anatomical abnormalities leading to SA [14]. In anatomically normal individuals, these surgical techniques have mixed success and are not routinely recommended.



   Homoeostasis in SA
Top
 Introduction
 Sleep apnoea
 Sleep studies
 Treatment options
 Homoeostasis in SA
SA in end-stage renal...
 Potential benefits from...
 References
 
The nocturnal polyuria of SA is an evoked response to conditions of negative intrathoracic pressure, due to inspiratory effort posed against a closed airway. The mechanism for this natriuretic response is the release of ANP due to cardiac distension caused by the negative pressure environment [16]. This cardiac hormone increases sodium and water excretion and also inhibits other hormone systems that regulate fluid volume, vasopressin and the renin–angiotensin–aldosterone complex [17]. At one extreme, proteinuria and occasionally nephrotic syndrome have been recognized in morbidly obese patients with SA. Renal biopsies of such patients have shown glomerulomegaly and focal segmental sclerosis. It is postulated that these lesions may result from increased glomerular filtration and blood flow [18].

The evidence that plasma volume is altered in OSA is indirect, based on the combination of reduced peripheral oedema, decreased water and sodium excretion and falling haematocrit, when apnoeas are eliminated with CPAP treatment [18]. In untreated OSA, sodium excretion is increased, as is vascular membrane permeability. There is a fluid shift from the plasma to the extra-cellular space, causing peripheral oedema, haemo-concentration and nocturnal polyuria. Increased ANP release, increased guanosine 3':5'-cyclic 6 monophosphate (cGMP) excretion, increased release of thromboxane and of endothelin and decreased renin–angiotensin–aldosterone activity, could be among the factors driving fluid redistribution in OSA [17]. Plasma angiotensin II and aldosterone are elevated in OSA and correlated with systemic hypertension. Figure 1 shows the interactions and potential mechanisms affecting outcomes seen in patients with ESRD and SA.


Figure 1
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  		Fig. 1. Schematic illustration of the homoeostatic interactions of OSA, CSA, PD and HD leading to increased mortality.

 


   SA in end-stage renal disease
Top
 Introduction
 Sleep apnoea
 Sleep studies
 Treatment options
 Homoeostasis in SA
 SA in end-stage renal...
Potential benefits from...
 References
 
Sleep disorders are common in ESRD patients treated with renal replacement therapy. They depress, affect and reduce self reported quality of life. Complaints about sleep are reported in up to 80% of patients and SA syndrome, restless legs syndrome (RLS) and periodic limb movement (PLM) disorder are much more prevalent than in the general population. Excessive daytime sleepiness is an important problem, reducing quality of life scores and functional health status in these patients.

Sleep disorders are equally prevalent in peritoneal dialysis (PD) and haemodialysis (HD) patients. Polysomnographic studies in patients on dialysis who complain of day-time fatigue or sleepiness reveal significant apnoeas in up to 73%. Potential complications include resistant hypertension, left ventricular concentric hypertrophy and diastolic dysfunction [19]. Moreover, nocturnal hypoxia associated with SA in ESRD patients is known to contribute to an increased risk of fatal and non-fatal cardiovascular events. A 1% decrease in average nocturnal saturation is associated with a 33% increase in the incident risk. The risk of cardiovascular events is five times higher in patients with average nocturnal SaO2 <95% [3].

Altered cardiovascular autonomic control is linked with nocturnal hypoxaemia and concentric left ventricular hypertrophy and may contribute to re-modelling seen in dialysis patients with its adverse consequences [19]. The severity of PLM and total arousals per hour of sleep are strongly associated with mortality in patients with ESRD with sleep disorders, independent of other factors and may be novel predictors.

ESRD patients with SA on PD have lower nocturnal arterial oxygen saturation during nights on PD than on other nights; hence PD may also adversely affect cardiovascular risk. Abnormalities in respiratory controller mechanisms related to chronic hypocarbia, metabolic acidosis and uraemic toxins, have been implicated in the occurrence of apnoea in this setting. The conversion from conventional (three times weekly) HD to six or seven times weekly nocturnal HD (NHD) is associated with a reduction in the frequency of apnoea and hypopnoea accompanied by increases in the minimal oxygen saturation, transcutaneous partial pressure of carbon dioxide and serum bicarbonate concentration.



   Potential benefits from treatment of SA in ESRD
Top
 Introduction
 Sleep apnoea
 Sleep studies
 Treatment options
 Homoeostasis in SA
 SA in end-stage renal...
 Potential benefits from...
References
 
SA can be treated effectively with CPAP in patients with ESRD. This may have a positive impact on survival and reduction in cardiovascular morbidity. The quality of sleep and nocturnal oxygenation have been shown to improve in ESRD patients treated with CPAP resulting in improved daytime alertness. CPAP may also prevent the progression of nephropathy by ameliorating glomerular hyperfiltration [18].

Long-term CPAP reduces blood pressure and plasma renin and angiotensin II levels [17]. Treatment of SA has been shown to reverse nocturnal polyuria and to reduce or eliminate nocturia and enuresis. Significant falls have been demonstrated in plasma BNP and urinary meta-adrenaline excretion in patients receiving adaptive ventilation [20]. This also reduces excessive daytime sleepiness in patients with Cheyne Stokes respiration and congestive cardiac failure [20].

Hypothetically the reduction in sympathomimetic drive, improvement in vagal tone and reduction in blood pressure surges during nocturnal apnoeas/hypopnoeas may reduce the well-known cardiovascular consequences in these patients and thus potentially reduce overall mortality in ESRD.

The awareness of a new potentially modifiable risk factor, i.e. SA in ESRD patients, is gradually increasing among renal physicians. With increasing awareness and a lower threshold for investigating the possibility of SA by arranging relatively inexpensive sleep studies in this group, these patients may have potential for appropriate beneficial treatment. There is still a need to increase the knowledge base about mechanisms and, therefore, avenues for improvement in the outcomes in this group of patients from CPAP therapy. More conclusive evidence of improvement in potential survival in this group of patients will be a prime motivator for healthcare resource allocation, and may reduce the burden of ‘non-renal replacement’ healthcare provision for ESRD patients.

In addition to CPAP, it is recognized that higher heart rates and impaired vagal and augmented sympathetic heart rate modulation during sleep in ESRD patients can be normalized by NHD. Potential mechanisms for these observations include attenuation of surges in sympathetic outflow elicited by apnoea and hypoxia during sleep, normalization of nocturnal breathing patterns that influence heart rate variability, and removal, by increased dialysis, of a sympathomimetic stimulus of renal origin. Blood pressure control may be improved along with nutrition, anaemia and quality of life.

Renal transplantation also improves nocturnal SA. However, compared with NHD and renal transplantation which are resource intense provisions, CPAP may provide a more cost-effective alternative for improvement in symptoms and survival, especially if the reported benefits on the rate of progression of nephropathy in patients with SA are confirmed.

Conflict of interest statement. None declared.



   References
Top
 Introduction
 Sleep apnoea
 Sleep studies
 Treatment options
 Homoeostasis in SA
 SA in end-stage renal...
 Potential benefits from...
 References
 

  1. Williams GW, Weller JM, Ferguson CW, Forsythe SB, Wu SC. (1983) Survival of endstage renal disease patients: age-adjusted differences in treatment outcomes. Kidney Int 24:691–693.[ISI][Medline]
  2. Powell C. (1997) Sleep apnea in end stage renal disease. Anna Journal 24:645–654.
  3. Zoccali C. (2000) Sleep apnoea and nocturnal hypoxaemia in dialysis patients: mere risk-indicators or causal factors for cardiovascular disease? Nephrol Dial Transplant 15:1919–1921.[Free Full Text]
  4. McCullough PA and Sandberg KR. (2003) B-type natriuretic peptide and renal disease. Heart Fail Rev 8:355–358.[CrossRef][ISI][Medline]
  5. Chakravorty I, Cayton RM, Szczepura A. (2002) Health utilities in evaluating intervention in the sleep apnoea/hypopnoea syndrome. Eur Respir J 20:1233–1238.[Abstract/Free Full Text]
  6. Wright J and White J. (2000) Continuous positive airways pressure for obstructive sleep apnoea. Cochrane Database Syst Rev CD001106:.
  7. Pressman MR, Benz RL, Schleifer CR, Peterson DD. (1993) Sleep disordered breathing in ESRD: acute beneficial effects of treatment with nasal continuous positive airway pressure. Kidney Int 43:1134–1139.[ISI][Medline]
  8. Stradling JR and Davies RJ. (2004) Sleep. 1: Obstructive sleep apnoea/hypopnoea syndrome: definitions, epidemiology, and natural history. Thorax 59:73–78.[Abstract/Free Full Text]
  9. De Backer WA. (1995) Central sleep apnoea, pathogenesis and treatment: an overview and perspective. [Review] [119 refs]. Eur Respir J 8:1372–1383.[Abstract]
  10. Fletcher EC. (1996) Obstructive sleep apnoea and cardiovascular morbidity. Monaldi Archives for Chest Disease 51:77–80.
  11. Elwood P, Hack M, Pickering J, Hughes J, Gallacher J. (2006) Sleep disturbance, stroke, and heart disease events: evidence from the Caerphilly cohort. J Epidemiol Community Health 60:69–73.[Abstract/Free Full Text]
  12. Engleman HM and Douglas NJ. (2004) Sleep. 4: Sleepiness, cognitive function, and quality of life in obstructive sleep apnoea/hypopnoea syndrome. Thorax 59:618–622.[Abstract/Free Full Text]
  13. Shneerson J and Wright J. (2001) Lifestyle modification for obstructive sleep apnoea (Cochrane Review). Cochrane Database Syst Rev 1:CD002875.
  14. Simonds AK. (2001) Managing obstructive sleep apnoea. Practitioner 245:117–120.[Medline]
  15. Hoekema A, Stegenga B, De Bont LG. (2004) Efficacy and co-morbidity of oral appliances in the treatment of obstructive sleep apnea-hypopnea: a systematic review. Crit Rev Oral Biol Med 15:137–155.[Abstract/Free Full Text]
  16. Krieger J, Schmidt M, Sforza E, et al. (1989) Urinary excretion of guanosine 3':5'-cyclic monophosphate during sleep in obstructive sleep apnoea patients with and without nasal continuous positive airway pressure treatment. Clin Sci 76:31–37.
  17. Saarelainen S, Hasan J, Siitonen S, Seppala E. (1996) Effect of nasal CPAP treatment on plasma volume, aldosterone and 24-h blood pressure in obstructive sleep apnoea. J Sleep Res 5:181–185.[CrossRef][ISI][Medline]
  18. Kinebuchi SI, Kazama JJ, Satoh M, et al. (2004) The short-term use of continuous positive airway pressure ameliorates glomerular hyperfiltration in patients with obstructive sleep apnea syndrome. Clin Sci 107:317–22.
  19. Zoccali C, Mallamaci F, Tripepi G, Benedetto FA. (2001) Autonomic neuropathy is linked to nocturnal hypoxaemia and to concentric hypertrophy and remodelling in dialysis patients. Nephrol Dial Transplant 16:70–77.[Abstract/Free Full Text]
  20. Kita H, Ohi M, Chin K, et al. (1998) The nocturnal secretion of cardiac natriuretic peptides during obstructive sleep apnoea and its response to therapy with nasal continuous positive airway pressure. J Sleep Res 7:199–207.[CrossRef][ISI][Medline]
Received for publication: 17. 6.06
Accepted in revised form: 24. 8.06


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