Effect of NAC on Sleep Apnea
Effect of NAC on Sleep Apnea
Sleep studies in ESRD patients have identified increased prevalence of Sleep Apnea. Based on
 current knowledge, treatment aimed at reducing oxidative stress might improve Sleep Apnea in
 HD patients. The aim of our study is to investigate the effect of N-acetylsysteine on Sleep
 Apnea in HD patients.
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 ].

 In our opinion, it is worth to check an ability of antioxidant therapy to produce a favorable
 effect on parameters of SA in dialysis patients.

 N-Acetylcysteine (NAC) is an active antioxidant proved to be safe and beneficial in
 hemodialysis patents [19]. In our recent study, NAC effectively reduced the ototoxic effect
 of gentamicin in chronic hemodialysis patients [20, 21]. Cheap and safe drug therapy may
 appear more cost effective than such resource consuming therapies as CPAP and not readily
 available treatments as prolong every night hemodialysis or kidney transplantation.

 The aim of our study is to investigate the effect of N-acetylsysteine on SA in HD patients.

 Methods. Study population. The study will include 20 patients with ESRD, treated with chronic
 hemodialysis in Assaf Harofeh Medical Center and suffering from sleep disturbances, such as
 frequent arousals, snoring, daytime sleepiness.

 Patients will be excluded from the study if they are:

 1. Recently started treated with chronic dialysis: less than 3 months.

 2. Survived recent major illness, requiring hospitalisation in the last 3 months.

 3. Patients with acute renal failure

 4. Currently treated with antioxidants ( NAC, vitamin E ets.)

 5. Current use of sleep pills Study protocol. We planned this study as a prospective
 cross-sectional study where every patient will serve as his/her own control. Al the
 patients will continue their previous dialysis and drugs regimen. The presence and
 severity of SA will be accessed using the overnight polysomnography in the Sleep
 Laboratory.

 After performance of baseline overnight polysomnography the patients will receive orally NAC
 1200 mg x 2/day for 4 weeks. At the end of this therapy, a follow up overnight
 polysomnography examination will be performed.

 The clinical monitoring of all the patients will include:

 1. Blood Pressure and Heart Rate - at each dialysis session 3 times a week. .

 2. Review of medications and doses.

 3. Body weight - at each dialysis session 3 times a week

 4. Dialysis adequacy: Kt/V at study start and end.

 5. Biochemical studies: full chemistry, bicarbonate, ADMA, DDAH, NO - both at baseline and
 follow up visits.

 Statistical analysis The statistical analysis will be performed using the statistical
 software SPSS-version 10. Parametric data will be expressed as means ± standard deviation and
 compared by the standard t-test. Non-parametric data will be compared using chi square test.
 p value of 0.05 or less will be considered significant.

 References

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 4. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of
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 NEJM 1993; 328:1230-35

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 Circulation 2003;108:9-12

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 who undergo nocturnal hemodialysis.

 N Engl J Med 2001; 344:102-7

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 end-stage renal disease after kidney transplantation. Am J Kidney Dis 1999;34:739-744

 14. Langevin B, Fougue D, Leger P, Robert D. Sleep apnea syndrome and end-stage renal
 disease. Cure after renal transplantation. Chest 1993;103:1330-1335

 15. Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous
 inhibitor of nitric oxide synthesis in chronic renal failure.

 Lancet. 1992 Mar 7;339(8793):572-5.

 16. Kielstein J, Boger R, Bode-Boger S et al. Asymmetric Dimethylarginine Plasma
 Concentrations Differ in Patients with End-Stage Renal Disease. J Am Soc Nephrol 1999;
 10:594-600

 17. Kielstein J, Zoccali C. Asymmetric dimethylarginine: a cardiovascular risk factor and a
 uremic toxin coming of age? Am J Kidney Dis. 2005;46(2):186-202.

 18. Saran R, Novak J, Desai A et al. Impact of vitamin E on plasma asymmetric
 dimethylarginine (ADMA) in chronic kidney disease (CKD): a pilot study.

 Nephrol Dial Transplant. 2003 Nov;18(11):2415-20.

 19. Tepel M, van der Giet M, Statz M et al. The antioxidant acetylcysteine reduces
 cardiovascular events in patients with end-stage renal failure: a randomized, controlled
 trial. Circulation. 2003 Feb 25;107(7):992-5.

 20. Feldman L, Efrati S, Abramsohn R, Yarovoy I, Gersch E, Eviatar E, Averbukh Z,
 Weissgarten J. N-Acetylcysteine for prevention of gentamicin-induced ototoxicity in
 hemodialysis patients. J Am Soc Nephrol 2006; 17 (Suppl): 22A

 21. Feldman L, Efrati S, Eviatar E, Abramsohn R, Yarovoy I, Gersch E, Averbukh Z,
 Weissgarten J. N-Acetylcysteine ameliorates gentamicin-induced ototoxicity in
 hemodialysis patients. Kidney Int 2007 ( in press)
Inclusion Criteria:

 -  The study will include 20 patients with ESRD, treated with chronic hemodialysis in
 Assaf Harofeh Medical Center and suffering from sleep disturbances, such as frequent
 arousals, snoring, daytime sleepiness.

 Exclusion Criteria:

 Patients will be excluded from the study if they are:

 -  Recently started treated with chronic dialysis: less than 3 months.

 -  Survived recent major illness, requiring hospitalisation in the last 3 months.

 -  Patients with acute renal failure

 -  Currently treated with antioxidants ( NAC, vitamin E ets.)

 -  Current use of sleep pills