Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT00592618 |
| Other study ID # |
346147SLEEP |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
N/A
|
| First received |
January 1, 2008 |
| Last updated |
January 11, 2008 |
Study information
| Verified date |
May 2007 |
| Source |
Assaf-Harofeh Medical Center |
| Contact |
Leonid S Feldman, MD |
| Phone |
+972-8-9779383 |
| Email |
leonidf[@]asaf.health.gov.il |
| Is FDA regulated |
No |
| Health authority |
Israel: Ministry of Health |
| Study type |
Interventional
|
Clinical Trial Summary
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.
Description:
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
1. United States Renal Data System. Patient mortality and survival. USRDS Annual Report.
Am J Kidney Dis 1997; 30 [Suppl. 1]: s91-s101
2. Chakravorty I, Shastry M, Farrington K. Sleep apnoea in end-stage renal disease: a
short review of mechanisms and potential benefit from its treatment. Nephrol Dial
Transplant 2007; 22:28-31
3. Kraus M, Hamburger R. Sleep apnea in renal failure. Adv Perit Dial 1997; 13:88-92
4. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of
sleep-disordered breathing among middle-aged adults.
NEJM 1993; 328:1230-35
5. Wolk R, Kara T, Somers V. Sleep-disordered breathing and cardiovascular disease.
Circulation 2003;108:9-12
6. Jung H, Han H, Lee J. Sleep apnea, coronary artery disease, and antioxidant status in
hemodialysis patients. AJKD 2005;45:875-882
7. Zoccali C. Sleep apnoea and nocturnal hypoxaemia in dialysis patients: mere
risk-indicators or causal factors for cardiovascular disease? Nephrol Dial Transplant
2000, 15:1919-21
8. Boaz M, Matas Z, Biro A, Katzir Z, Green M, Fainaru M, Smetana S. Serum malondialdehyde
and prevalent cardiovascular disease in hemodialysis. Kidney Int 1999;56:1078-83
9. Lavie L. Obstructive sleep apnoea syndrome--an oxidative stress disorder. Sleep Med Rev
2003;7:35-51
10. D'Ambrosio C, Bowman T, Mohsenin V. Quality of life in patients with obstructive sleep
apnea: effect of nasal continuous positive airway pressure--a prospective study.Chest
1999;115:123-29
11. Pressman M, Benz R, Schleifer C, Peterson D. Sleep disordered breathing in ESRD: acute
beneficial effects of treatment with nasal continuous positive airway pressure. Kidney
Int 1993; 43:1134-39.
12. Hanly P, Pierratos A. Improvement of sleep apnea in patients with chronic renal failure
who undergo nocturnal hemodialysis.
N Engl J Med 2001; 344:102-7
13. Auckley D, Schmidt-Nowara W, Brown L. Reversal of sleep apnea hypopnea syndrome in
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)
