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NDT Advance Access originally published online on June 7, 2007
Nephrology Dialysis Transplantation 2007 22(10):3028-3033; doi:10.1093/ndt/gfm309
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org


Impact of kidney transplantation on sleep apnoea in patients with end-stage renal disease

Jaime M. Beecroft1, Jeffrey Zaltzman2, Ramesh Prasad2, Galo Meliton2 and Patrick J. Hanly1

1Department of Medicine, University of Calgary, Alberta and 2Department of Medicine, University of Toronto, Ontario, Canada

Correspondence and offprint requests to: Patrick J. Hanly, 1421 Health Sciences Center, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1. Email: phanly{at}ucalgary.ca



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Sleep apnoea is common in patients with end-stage renal disease. Although individual case reports have described an improvement in sleep apnoea following kidney transplantation, there have been no longitudinal studies of a case series to determine what proportion of patients with sleep apnoea improve.

Methods. Dialysis-dependent patients awaiting kidney transplantation and pre-dialysis patients with an identified living donor kidney had overnight polysomnography, which was repeated several months after successful kidney transplantation. Patients were divided into apnoeic and non-apnoeic groups based on an apneoa-hypopnoea index (AHI) > 10/h during pre-transplant polysomnography and, following transplantation, apnoeic patients were further divided into responders and non-responders based on >50% reduction in AHI and/or AHI < 10/h.

Results. Eighteen patients (11 men, 7 women), aged 27–65, were studied. Pre-transplant sleep apnoea was present in 11 of 18 (61%) patients. Although transplantation was associated with a significant reduction in blood urea nitrogen and serum creatinine, there were no significant changes in AHI (pre vs post: 20.2 ± 15.1 vs 23.5 ± 21.3). Among the 11 apnoeic patients, only three met the criteria for a significant improvement (‘responder’). There were no patient characteristics, sleep apnoea indices or renal function changes that distinguished responders from non-responders.

Conclusions. Sleep apnoea improves in a minority of patients with end-stage renal disease following successful kidney transplantation. Specific determinants of improvement were not identified.

Keywords: end-stage renal disease; kidney transplantation; polysomnography; sleep apnoea; sleep-disordered breathing



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Sleep apnoea is a chronic medical disorder characterized by the recurrent cessation of breathing during sleep. Obstructive sleep apnoea (OSA) is caused by upper airway narrowing and occlusion and central sleep apnoea results from a transient loss of respiratory effort. Sleep apnoea is characteristically associated with repetitive episodes of hypoxia, hypercapnia and arousal from sleep, which results in impaired daytime function and an increased risk of cardiovascular disease, particularly hypertension [1]. Although sleep apnoea may be suspected from the clinical assessment of an individual patient, overnight polysomnography is required to confirm the diagnosis and establish its severity [2]. Polysomnography is considered the ‘gold standard’ for assessment of sleep apnoea since diagnosis following clinical evaluation alone is unreliable [3].

While the prevalence of sleep apnoea in the general population is approximately 2–4% [4], it has been reported to be greater than 50% in patients with end-stage renal disease (ESRD) [5]. Patients with ESRD can develop central sleep apnoea [6–8], but the most common form of sleep-disordered breathing in this patient population is OSA[9]. Obstructive sleep apnoea may exacerbate some of the daytime symptoms of ESRD, including excessive sleepiness, cognitive impairment and fatigue [10–12]. In addition, OSA has the potential to increase the cardiovascular complications associated with ESRD, which are the leading causes of morbidity and mortality in this patient population [13]. The high prevalence of OSA in ESRD combined with the strong association with daytime dysfunction and cardiovascular disease makes it an important comorbidity with the potential to alter clinical outcomes in this patient population.

Current literature suggests that both OSA and central sleep apnoea are corrected following successful kidney transplantation [14,15]. However, this literature is limited to a few case reports and there have been no longitudinal case series that have systematically evaluated the change in sleep apnoea following kidney transplantation. We tested the hypothesis that kidney transplantation corrects sleep apnoea in patients with ESRD. The primary objective of our study was to determine whether the prevalence and severity of sleep apnoea improved following kidney transplantation. Our secondary objective was to identify predictors of improvement.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Patient recruitment and study protocol
Patients attending the Transplant Clinic at St. Michael's Hospital were invited to participate in the study. Potential recruits were either dialysis-dependent patients who were awaiting kidney transplantation or pre-dialysis patients with an identified living donor kidney. Patients suspected of having sleep apnoea by their attending nephrologist were referred to the Sleep Laboratory for further assessment. Baseline evaluation prior to kidney transplantation consisted of overnight attended polysomnography and clinical evaluation. Patients receiving haemodialysis underwent polysomnography within 24 h of their last dialysis session. Patients receiving peritoneal dialysis (continuous cycler-assisted peritoneal dialysis nocturnally with 3–5 exchanges during sleep and/or 3–5 manual exchanges throughout the day with a single exchange overnight) continued dialysis during polysomnography. A venous blood sample (3–5 ml) was drawn to determine blood urea nitrogen (BUN) and serum creatinine. A detailed history of each patient's renal failure was obtained, including the cause of renal failure, duration of treatment and dialysis schedule for those receiving renal replacement therapy. Polysomnography was repeated following successful kidney transplantation. The study protocol was reviewed and approved by the research ethics board at St. Michael's Hospital and all patients gave informed written consent to participate in the study.

Polysomnography
Overnight attended polysomnography was performed in the Sleep Laboratory by continuous monitoring of the electroencephalogram, electrooculogram and sub-mental electromyogram, electrocardiogram, nasal airflow (Ultima Dual Airflow Pressure Sensor, Braebon Medical Corporation, Kanata, ON,Canada), chest and abdominal respiratory movements (Respitrace, Ambulatory Monitoring; Ardsley, NY, USA), oximetry (Mallinckrodt/Nellcor Puritan Bennett, Hazelwood, MO, USA) and body position. Recordings were performed and scored by registered polysomnographic technologists according to published criteria [16]. Arousal was defined as a simultaneous increase in alpha activity on the EEG, EMG activation and eye movements that lasted for 3–15 s. Awakening was scored if these changes persisted for more than 15 s. Apnoea was defined as absence of airflow for more than 10 s and hypopnoea was defined as a reduction in airflow for more than 10 s associated with an arousal and/or reduction in oxygen saturation >3%. These events were further classified as central if abdominal and ribcage movements were synchronous, obstructive if the movements were paradoxical and mixed if a central event had terminal obstructive features. The apnoea-hypopnoea index (AHI) was defined as the number of apnoeas and hypopnoea per hour of sleep. Mean oxygen saturation (SaO2) was calculated by averaging the high and low values for each 30 s epoch of sleep. Patients were divided into apnoeic and non-apnoeic groups based on AHI > 10 events/h during pre-transplant polysomnography. Apnoeic and non-apnoeic groups were compared at baseline to identify risk factors for sleep apnoea and to assess the relative contribution of sleep apnoea to sleep disruption in this patient population. Non-apnoeic patients were followed post transplant as a control group to determine whether the prevalence of sleep apnoea changes over time following kidney transplantation.

Analysis
Mean data and SD were analysed using independent samples t-test and repeated measures analysis of variance. Nominal data were analysed using {chi}2 analysis. All statistical analysis was performed using computer software (SPSS 14.0 for Windows, SPSS Inc., Chicago, IL, USA). All P values <0.05 were considered statistically significant.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Eighteen patients (11 men, 7 women), aged 27–65, were studied (Table 1). Sleep apnoea was present in 11 patients (61%). Gender distribution, age and body mass index (BMI) were similar between apnoeic and non-apnoeic groups. Chronic glomerulonephritis was the most common cause of ESRD, followed by polycystic kidney disease, diabetes, hypertension and reflux nephropathy. In two patients the cause of ESRD was unknown. Prior to kidney transplantation, 11 patients were receiving haemodialysis, one patient was receiving peritoneal dialysis and six patients pre-dialysis. Baseline measurements of BUN and serum creatinine were similar between apnoeic and non-apnoeic groups and kidney transplantation was associated with a significant reduction in BUN and serum creatinine in both groups (Table 2). There were no significant changes in weight, BMI, neck circumference or neck circumference indexed to patient height following transplantation.


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  		Table 1. Patient Demographics

 

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  		Table 2. Renal function and morphology pre-and post-kidney transplantation

 
By definition, the AHI was significantly greater in the apnoeic than non-apnoeic group prior to transplantation (Table 3). Apnoeas and hypopnoeas were predominantly obstructive, with a smaller proportion classified as central or mixed events. In each patient the majority (>65%) of respiratory events had obstructive features. The frequency of arousals was significantly higher in apnoeic patients and the majority (56%) were associated with respiratory events. The frequency of awakenings was similar between apnoeic and non-apnoeic groups. Mean SaO2 was not significantly different between groups. Apnoeic patients tended to have a lower sleep efficiency and less slow wave sleep, although these differences did not reach statistical significance. Following kidney transplantation, AHI, arousal and awakening frequency and mean SaO2 did not change significantly (Table 3). Although most parameters of sleep architecture did not change, there was a significant decrease in the proportion of slow wave sleep following transplantation.


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  		Table 3. Polysomnography

 
Apnoeic patients were further classified as ‘responders’ if AHI fell >50% and/or was reduced to <10 events/h post transplant. Only three out of 11 patients (27%) with sleep apnoea met these criteria in whom AHI fell from 20.4 ± 15.4 to 7.2 ± 6.8 events/h (Table 4, Figure 1). This reduction was associated with a trend for a decrease in the frequency of arousals, an increase in mean SaO2 and an improvement in sleep efficiency, although these changes did not reach significance. Gender distribution, pre-transplant age, AHI and mean SaO2 were similar between responders and non-responders. Furthermore, BMI, neck circumference and neck circumference indexed to patient height were similar between responders and non-responders and did not change significantly post-transplant (Table 5). The reduction in BUN and serum creatinine following transplantation was similar between responders and non-responders and there was no difference in the duration that patients were treated with dialysis or in the time between transplantation and follow-up polysomnography.


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  		Table 4. Polysomnography in apnoeic responders and non-responders pre- and post-kidney transplantation

 

Figure 1
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  		Fig. 1. Change in apnoea-hypopnoea index following kidney transplantation (post) in patients with apnoea-hypopnoea index >10 prior to transplantation (pre). Only 3 of 11 patients showed significant improvement (responder). Mean data ± SD pre and post are indicated by outside vertical bars.

 

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  		Table 5. Patient morphology and renal replacement therapy in apnoeic responders and non-responders pre- and post-kidney transplantation

 


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
The previous literature on this topic consists of two case reports that describe the reversal of sleep apnoea following kidney transplantation. One report describes a remarkable improvement in the severity of sleep apnoea following kidney transplantation in two patients (one with OSA and one with central sleep apnoea) assessed by overnight polysomnography [15]. Similar results were subsequently reported in another patient with OSA assessed by home oximetry [14]. This may create the impression that kidney transplantation corrects sleep apnoea in all patients with ESRD. The current study is the first polysomnographic evaluation of sleep apnoea performed on a series of patients before and after successful treatment of ESRD by kidney transplantation. Contrary to what has been reported previously, the majority of our patients continued to have OSA. Less than 30% met our criteria for a significant improvement in apnoea severity (responders), despite restoration of kidney function close to normal in all patients. We were unable to identify factors that distinguished responders from non-responders, although such comparisons may be limited by the small number of responders in this study.

In the general population, obesity and large neck circumference are risk factors for the development of OSA [17]. In our patients, BMI and neck circumference tended to increase following transplantation, which can promote the development of OSA and thereby diminish any improvement associated with the correction of uraemia by kidney transplantation. However, weight gain does not fully explain our findings since these changes were similar between responders and non-responders. Renal function was restored close to normal in both responders and non-responders following transplantation. Consequently, the presence of OSA post-transplantation is not explained by persistent uraemia or on-going renal dysfunction in our patients. Another possible explanation for the lack of improvement in all of our patients is that correction of sleep apnoea following kidney transplantation is time-dependant. However, the duration between transplantation and follow-up polysomnography was similar between responders and non-responders; if anything, follow up was performed later in non-responders, which is against a bias that non-responders were re-assessed too soon after transplantation.

Sleep apnoea that pre-dates the onset of chronic renal failure would not be expected to improve following transplantation, which may partially explain our findings. Unfortunately, our study protocol did not include the data required to address this possibility. However, sleep apnoea in our patients does not appear to be related to etiological factors associated with OSA in the general population since age, gender, BMI and neck circumference were similar between apnoeic and non-apnoeic groups and between apnoeic responders and non-responders. Furthermore, the high prevalence of sleep apnoea in patients with ESRD and the weak association with age, gender and BMI [7,11,18,19] suggest its pathophysiology is related to factors that are uniquely associated with the development of chronic renal failure. Sleep apnoea may also develop in patients with ESRD due to comorbid medical conditions such as congestive heart failure [20,21] or diabetes mellitus [22]. Our patients did not have congestive heart failure and two of three patients with diabetic nephropathy showed significant improvements in AHI following transplantation. Consequently, the development of OSA in our patients does not appear to be associated with pre-existing comorbid disease.

The results of this study have important clinical implications. Repeated arousals and awakenings associated with apnoea result in sleep disruption, sleep loss and excessive daytime sleepiness. Obstructive sleep apnoea may therefore contribute to the high prevalence of sleep-related complaints reported in kidney transplant recipients [23–25]. There was a trend for a higher frequency of respiratory arousals in apnoeic non-responders following transplantation (Table 4), suggesting that persistent OSA does contribute to sleep disruption. In the general population, OSA is associated with an increased risk of cardiovascular disease, particularly hypertension [1]. Hypertension is an independent risk factor for allograft dysfunction [26,27] and cardiovascular mortality [28] in kidney transplant recipients. Cardiovascular disease remains the leading cause of mortality in this patient population [28]. Recent findings suggest that sleep apnoea is associated with increased mortality in dialysis-dependent patients [29]. Obstructive sleep apnoea which persists following transplantation may therefore contribute to the increased risk of cardiovascular disease and reduced life expectancy among kidney transplant recipients [30,31]. Treatment of OSA by the application of continuous positive airway pressure has been shown to improve daytime sleepiness [32] and decrease blood pressure [33,34] in patients with normal renal function. Our findings highlight the potential clinical consequences of persistent sleep apnoea in this patient population and the need for comprehensive re-evaluation of sleep apnoea following kidney transplantation.

In summary, OSA improves in less than 30% of patients with ESRD following successful kidney transplantation. Persistent sleep apnoea may contribute both to sleep-related symptoms and the risk of cardiovascular disease in this patient population. Further research is required to determine how kidney transplantation may improve sleep apnoea and to establish identifiable predictors of this response.

Conflict of Interest Statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med (2000) 342:1378–1384.[Abstract/Free Full Text]
  2. Polysomnography Task Force, American Sleep Disorders Association Standards of Practice Committee. Practice parameters for the indications for polysomnography and related procedures. Sleep (1997) 20:406–422.[Web of Science][Medline]
  3. Viner S, Szalai JP, Hoffstein V. Are history and physical examination a good screening test for sleep apnea? Ann Intern Med (1991) 115:356–359.[CrossRef][Web of Science][Medline]
  4. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med (1993) 328:1230–1235.[Abstract/Free Full Text]
  5. Kraus MA, Hamburger RJ. Sleep apnea in renal failure. Adv Perit Dial (1997) 13:88–92.[Medline]
  6. Hanly PJ, Pierratos A. Improvement of sleep apnea in patients with chronic renal failure who undergo nocturnal hemodialysis. N Engl J Med (2001) 344:102–107.[Abstract/Free Full Text]
  7. Kimmel PL, Miller G, Mendelson WB. Sleep apnea syndrome in chronic renal disease. Am J Med (1989) 86:308–314.[CrossRef][Web of Science][Medline]
  8. Mendelson WB, Wadhwa NK, Greenberg HE, Gujavarty K, Bergofsky E. Effects of hemodialysis on sleep apnea syndrome in end-stage renal disease. Clin Nephrol (1990) 33:247–251.[Web of Science][Medline]
  9. Beecroft J, Duffin J, Pierratos A, Chan CT, McFarlane P, Hanly PJ. Enhanced chemo-responsiveness in patients with sleep apnoea and end-stage renal disease. Eur Respir J (2006) 28:151–158.[Abstract/Free Full Text]
  10. Murray AM, Tupper DE, Knopman DS, et al. Cognitive impairment in hemodialysis patients is common. Neurology (2006) 67:216–223.[Abstract/Free Full Text]
  11. Hanly P. Sleep apnea and daytime sleepiness in end-stage renal disease. Semin Dial (2004) 17:109–114.[CrossRef][Web of Science][Medline]
  12. Weisbord SD, Fried LF, Arnold RM, et al. Prevalence, severity, and importance of physical and emotional symptoms in chronic hemodialysis patients. J Am Soc Nephrol (2005) 16:2487–2494.[Abstract/Free Full Text]
  13. Bloembergen WE, Port FK, Mauger EA, Wolfe RA. A comparison of cause of death between patients treated with hemodialysis and peritoneal dialysis. J Am Soc Nephrol (1995) 6:184–191.[Abstract]
  14. Auckley DH, Schmidt-Nowara W, Brown LK. Reversal of sleep apnea hypopnea syndrome in end-stage renal disease after kidney transplantation. Am J Kidney Dis (1999) 34:739–744.[Web of Science][Medline]
  15. Langevin B, Fouque D, Leger P, Robert D. Sleep apnea syndrome and end-stage renal disease. Cure after renal transplantation. Chest (1993) 103:1330–1335.[CrossRef][Web of Science][Medline]
  16. Rechtschaffen A, Kales A. A manual of standarized terminology, techniques and scoring system for sleep stages of human subjects. (1968) CA, USA: Brain Information Service/Brain Research Institute, University of California at Los Angeles. (NIH publication no. 204).
  17. Young T, Peppard PE, Taheri S. Excess weight and sleep-disordered breathing. J Appl Physiol (2005) 99:1592–1599.[Abstract/Free Full Text]
  18. Jean G, Piperno D, Francois B, Charra B. Sleep apnea incidence in maintenance hemodialysis patients: influence of dialysate buffer. Nephron (1995) 71:138–142.[Web of Science][Medline]
  19. Stepanski E, Faber M, Zorick F, Basner R, Roth T. Sleep disorders in patients on continuous ambulatory peritoneal dialysis. J Am Soc Nephrol (1995) 6:192–197.[Abstract]
  20. Javaheri S, Parker TJ, Wexler L, et al. Occult sleep-disordered breathing in stable congestive heart failure. Ann Intern Med (1995) 122:487–492.[Abstract/Free Full Text]
  21. Sin DD, Fitzgerald F, Parker JD, Newton G, Floras JS, Bradley TD. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med (1999) 160:1101–1106.[Abstract/Free Full Text]
  22. West SD, Nicoll DJ, Stradling JR. Prevalence of obstructive sleep apnoea in men with type 2 diabetes. Thorax (2006) 61:945–950.[Abstract/Free Full Text]
  23. Eryilmaz MM, Ozdemir C, Yurtman F, Cilli A, Karaman T. Quality of sleep and quality of life in renal transplantation patients. Transplant Proc (2005) 37:2072–2076.[CrossRef][Web of Science][Medline]
  24. Novak M, Molnar MZ, Ambrus C, et al. Chronic insomnia in kidney transplant recipients. Am J Kidney Dis (2006) 47:655–665.[CrossRef][Web of Science][Medline]
  25. Sabbatini M, Crispo A, Pisani A, et al. Sleep quality in renal transplant patients: a never investigated problem. Nephrol Dial Transplant (2005) 20:194–198.[Abstract/Free Full Text]
  26. Mange KC, Cizman B, Joffe M, Feldman HI. Arterial hypertension and renal allograft survival. JAMA (2000) 283:633–638.[Abstract/Free Full Text]
  27. Opelz G, Wujciak T, Ritz E. Association of chronic kidney graft failure with recipient blood pressure. Collaborative Transplant Study. Kidney Int (1998) 53:217–222.[CrossRef][Web of Science][Medline]
  28. Arend SM, Mallat MJ, Westendorp RJ, van der Woude FJ, van Es LA. Patient survival after renal transplantation; more than 25 years follow-up. Nephrol Dial Transplant (1997) 12:1672–1679.[Abstract/Free Full Text]
  29. Charest A, Hanly PJ, Parkes RK, Logan AG, Naimark DMJ. Impact of sleep apnea on mortality in patients with end-stage renal disease [abstract]. J Am Soc Nephrol (2004) 15:A637.
  30. Ojo AO. Cardiovascular complications after renal transplantation and their prevention. Transplantation (2006) 82:603–611.[Web of Science][Medline]
  31. Ojo AO, Hanson JA, Wolfe RA, Leichtman AB, Agodoa LY, Port FK. Long-term survival in renal transplant recipients with graft function. Kidney Int (2000) 57:307–313.[CrossRef][Web of Science][Medline]
  32. Kryger MH. Management of obstructive sleep apnea. Clin Chest Med (1992) 13:481–492.[Web of Science][Medline]
  33. Mayer J, Becker H, Brandenburg U, Penzel T, Peter JH, Von WP. Blood pressure and sleep apnea: results of long-term nasal continuous positive airway pressure therapy. Cardiology (1991) 79:84–92.[Web of Science][Medline]
  34. Becker HF, Jerrentrup A, Ploch T, et al. Effect of nasal continuous positive airway pressure treatment on blood pressure in patients with obstructive sleep apnea. Circulation (2003) 107:68–73.[Abstract/Free Full Text]
Received for publication: 21.12.06
Accepted in revised form: 24. 4.07


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