Effect of NAC on Sleep Apnea

Background Cardiovascular disease is the commonest cause of morbidity and mortality in chronic dialysis patients [1]. Sleep studies in ESRD patients have identified increased prevalence of sleep apnea (SA), both obstructive (OSA) and central (CSA) in origin [2]. The reported prevalence of SA in patients with ESRD ranges from 50% to 70% [3], which is dramatically higher than the estimated prevalence of 2% to 4% in the general population [4]. SA has been recognized as a novel risk factor for cardiovascular disease in general population [5]. Recent evidence showed that severity of SA in hemodialysis patients is associated with severity of coronary artery calcifications [6]. Underlying mechanisms by which SA adversely affects cardiovascular morbidity and mortality have not been fully established yet. The presence of untreated SA may further impair fluid balance, cardiovascular function and increase mortality through abnormal vagal or sympatomimetic responces and hypoxia [7]. One intriguing possibility is oxidative stress, which has been implicated in cardiovascular disease in patients with ESRD [8]. Recent study demonstrated association between SA and decreased antioxidant status in hemodialysis patients [6]. Repeated apnea-related hypoxic events in patients with SA may trigger elevated oxidative stress [9].

In general population, the treatment of SA with CPAP improves oxygenation during sleep and quality of life [10]. In the ESRD population, CPAP was used in a very preliminary study on 8 patients with some improvement in nocturnal oxygenation and 5 of 6 patients reported improved daytime alertness [11]. Unfortunately, CPAP application itself may be stressful, poorly tolerated and so disturb night sleep.

Hanly and Pierratos suggested that SA in hemodialysis patients may be a consequence of inadequate treatment of uremia by standard 4-hours thrice-weekly HD procedure [12]. This group reported that intensive nocturnal HD for 8 hours 6-7 times per week reduced the severity of SA, although their patients continued to suffer from frequent arousals, diminished sleep time, REM sleep and sleep efficiency [12]. Restoration of normal kidney function by transplantation may lead to reversal of SA [13, 14].

Several experimental and clinical studies showed that increased oxidative stress in dialysis patients may be due to inhibition of nitric oxide (NO) synthesis by ADMA (Asymmetric Dimethylarginine ), known to be endogenous inhibitor of NO synthetase [15]. ADMA may be significantly reduced by dialysis [16]. Metabolism of ADMA is primarily by the enzyme DDAH , which activity is decreased by inflammation, oxidative stress, diabetes mellitus and hypercholesterolemia [17 ]. It was proposed that circulating ADMA may be one mechanism accounting for the resistant hypertension and overfluid in dialysis patients [17 ].

Based on current knowledge, treatment aimed at reducing oxidative stress should decrease ADMA levels [17 ], and it is logical to suggest that such a therapy might improve SA in HD patients. One preliminary study on effect of antioxidant Vitamin E showed a small beneficial effect on ADMA in chronic kidney disease [19 ].