Sleep apnoea and nocturnal hypoxaemia in dialysis patients: mere risk-indicators or causal factors for cardiovascular disease?

Carmine Zoccali

CNR Centro Fisiologia Clinica and Divisione di Nefrologia Ospedali Riuniti, Reggio Cal, Italy

Epidemiology of sleep apnoea in the general population and in dialysis patients

Estimates of the prevalence of sleep apnoea syndrome (SA) in the general population give widely different figures, ranging from 0.3 to 8.5% [13]. This is probably because of differences in definitions, in the design of the studies and the investigations performed as well as in the age, sex and other characteristics of the populations surveyed. The prevalence of this disturbance in patients on chronic dialysis is still uncertain but available estimates indicate that it may be at least five times higher than that in the general population [48]. Snoring is the symptom that usually alerts the physician to suspect SA. Restless sleep, frequent arousal, daytime somnolence, headaches and fatigue are all common complaints of patients with SA which may be mistakenly attributed to chronic renal failure. Perhaps the main reason why SA is important in nephrology is that it is associated with various cardiovascular complications ranging from cardiac ischaemia, left ventricular hypertrophy and arrhythmia to cardiorespiratory arrest [913]. Although the potential contribution of SA to cardiovascular complications in patients with advanced renal diseases seems likely [14], until now evidence in support of this hypothesis is very scanty. Importantly, if SA is causally related to the high cardiovascular risk of renal failure, it would represent a relevant target for intervention because it is well known that continuous positive airway pressure reverses SA in dialysis patients [4].

Why is SA so frequent in dialysis patients?

The high frequency of SA in renal failure is in part explained by the fact that the most common causes of end-stage renal disease (ESRD), namely atherosclerosis and diabetes, are also independently associated with this syndrome. Risk factors for SA also include male sex, obesity, cranio-facial abnormalities and a family history of SA but these factors explain only in part the exceedingly high prevalence of SA in the dialysis population. Thus, there is little doubt that uraemia per se is associated with SA [47]. The mechanisms responsible for SA remain largely unknown and several theories have been proposed. Metabolic acidosis leading to unstable respiratory control is considered a potential cause. Accumulation of toxic substances that may destabilize breathing during sleep is another possibility but studies examining the effect of dialysis on SA have produced mixed results. Other potential factors include anaemia, osmotic disequilibrium, uraemic neuropathy and alterations in cytokine levels [57]. The observation that SA is at least partly reversible after renal transplantation is convincing proof that SA may be a direct consequence of renal failure [6].

SA and cardiovascular risk in renal failure

SA increases morbidity and mortality related to hypertension, cardiac ischaemia, arrhythmia, and stroke. Because coronary artery disease and stroke are the leading causes of mortality in the ESRD population, it is advisable that the nephrologist pays particular attention to identifying SA as a risk factor in ESRD patients under his/her care.

There is consistent evidence in the general population that the high cardiovascular risk associated with SA depends mainly on enhanced sympathetic tone triggered by episodes of nocturnal hypoxaemia. Intermittent hypoxia causes sympathetic activation that outlasts the triggering stimulus [15]: as a result the systemic consequences of episodic hypoxia may be long lasting. Fletcher et al. [16] observed that norepinephrine excretion is high in patients with SA and this finding is in line with this scenario. On the other hand SA has been observed in insulin resistance [17]. The role of the sympathetic system in the genesis of hypertension, cardiac hypertrophy and cardiovascular risk is well-established [18]. Insulin resistance is a common finding in the uraemic population and it is thought that this alteration contributes to the high cardiovascular morbidity and mortality of these patients. Furthermore, hypoxaemia causes endothelial distress leading to enhanced synthesis of endothelin as well as to a reduced synthesis of nitric oxide. Thus, episodes of nocturnal hypoxaemia in SA trigger alterations in endothelial function which favour hypertension and vascular damage. Notably, a defect in endothelium-dependent vascular relaxation is demonstrable in hypertensive patients with obstructive sleep and this defect is largely independent of hypertension [19]. The vascular pathogenetic link between obstructive SA and systemic hypertension may have peculiar implications in chronic renal failure, a situation where endothelial cell damage is almost universal.

Episodes of nocturnal hypoxaemia (the effector mechanism whereby SA influences cardiovascular control), are in part responsible for nocturnal hypertension in dialysis patients [20]. It is interesting to note that nocturnal hypoxaemia is even more strongly associated with concentric hypertrophy and remodelling [20,21] and that this linkage is largely independent of day time and night time arterial pressure. Concentric hypertrophy is a strong predictor of death [22], therefore nocturnal hypoxaemia might contribute to the high rate of death in ESRD. Notably, nocturnal hypoxaemia in dialysis patients is also associated with altered parasympathetic and sympathetic function (Zoccali C, Mallamaci F, Tripepi G, Benedetto FA, submitted for publication). Since alterations in the chemosensory control of the respiration are paralleled by altered autonomic control of the cardiovascular system [23] it appears likely that a common mechanism explains both disturbed respiratory control during night and autonomic dysfunction. Although several factors may independently affect cardiovascular and respiratory control in dialysis patients, we speculated that the prime suspects are substances of the endogenous opioid class like the µ-receptor agonist metenkephalin [24]. Such an opioid interferes with the parasympathetic control of the heart in man [25]. Since integrity of the parasympathetic system is of paramount importance for the prevention of arrhythmias and cardiac arrest, it is possible that dysautonomia represents a mechanism mediating the adverse cardiovascular effects of nocturnal hypoxaemia.

Why are SA and nocturnal hypoxaemia in dialysis patients so often overlooked?

The diagnosis of SA requires polysomnographic studies. Several screening methods of varying complexity have been proposed. Although nocturnal pulse oximetry has a sensitivity of 98% [26], at present no test can reliably replace polysomnography. The necessity of resorting to polysomnographic studies is perhaps one of the main reasons why the nephrologist rarely pursues the diagnosis of SA. Such studies require that the patient be examined in the sleep laboratory. Some experts demand a two-night hospital stay to confirm/exclude the diagnosis. The cost of one night in the sleeping laboratory far exceeds $1000. Many dialysis patients refuse to undergo sleep studies. Furthermore, in most academic centres sleep laboratories are fully booked months ahead. Thus the organizational effort demanded to the nephrology staff for arranging sleep studies may be prohibitive.

While it is unquestionable that the formal diagnosis of SA requires adequate polysomnographic studies, we ought to be aware that nocturnal hypoxaemia rather than disturbed sleep is the trigger of the adverse cardiovascular effects of sleep apnoea. Thus the nephrologist who aims at appreciating the cardiovascular risk deriving from nocturnal hypoxaemia may rely on good quality recordings of nocturnal pulse oximetry at home. This technique has been used in a recent study in dialysis patients [27]. Given the high frequency of SA in uraemic patients with symptoms suggestive of SA [4], it is extremely likely that the finding of repeated episodes of nocturnal hypoxaemia in these patients indicates the presence of true SA. However, negative studies have a relatively low negative prediction power [26]. The reliability of nocturnal hypoxaemia for the diagnosis of SA in dialysis patients ought to be better defined. Reliable techniques for the screening [28] and diagnosis [29] of SA at home are now emerging. Pulse oximetry, which is a very reproducible technique for the detection of episodes of nocturnal hypoxia [30], may be confidently used in studies aimed at linking SA to cardiovascular risk in patients with chronic renal failure.

Nocturnal hypoxaemia represents a potentially important novel cardiovascular risk factor in dialysis patients. The risk is presumably indicated by increased sympathetic activity, by insulin resistance and/or by endothelial cell dysfunction. Observational and intervention studies are needed to test the hypothesis that SA and the attendant nocturnal hypoxaemia are causally associated with cardiovascular risk in dialysis patients. A variety of treatments are now available for SA, but nasal continuous positive airway pressure (CPAP) is the treatment of choice. The attractive hypothesis that CPAP might abrogate cardiovascular damage in well-selected patients with chronic renal diseases should be tested.

Notes

Correspondence and offprint requests to: C. Zoccali, CNR Centro Fisiologia Clinica, Via Sbarre Inferiori 39, I-89100, Reggio Cal, Italy. Back

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