http://informahealthcare.com/ceh ISSN: 1064-1963 (print), 1525-6006 (electronic) Clin Exp Hypertens, 2014; 36(4): 211–216 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10641963.2013.804546
ORIGINAL ARTICLE
Obstructive sleep apnea syndrome and chronic kidney disease: a new cardiorenal risk factor Abdullah Ozkok1, Asiye Kanbay2, Ali Riza Odabas1, Adrian Covic3, and Mehmet Kanbay1 Division of Nephrology, Department of Internal Medicine and 2Department of Pulmonary Medicine, Istanbul Medeniyet University School of Medicine, Istanbul, Turkey, and 3Nephrology Clinic, Dialysis and Renal Transplant Center, ‘C.I. PARHON’ University Hospital, ‘Gr. T. Popa’ University of Medicine and Pharmacy, Iasi, Romania
Clin Exp Hypertens Downloaded from informahealthcare.com by Nyu Medical Center on 10/12/14 For personal use only.
1
Abstract
Keywords
Clinical and experimental studies revealed that sleep apnea might be an insidious risk factor for the progression of kidney disease and development of cardiovascular events by exacerbating well-known risk factors, namely hypertension, type 2 diabetes mellitus and obesity. Furthermore, sleep apnea also has a negative impact on endothelial function. Therefore, sleep apnea might be defined as a new cardiorenal risk factor. In this review, we aimed to summarize the evidences supporting the complex inter-relations between sleep apnea and development and progression of chronic kidney disease.
Chronic kidney disease, hypertension, inflammation, sleep apnea
General considerations Obstructive sleep apnea syndrome (OSAS) is a potentially life-threatening disorder characterized by repeated episodes of apnea–hypopnea due to upper airway obstruction. OSAS is a common disease affecting approximately 5–20% of the general population, but it is generally under-diagnosed (1–3). Frequency of sleep apnea has been reported to be 50–70% in patients with end-stage renal disease (ESRD) (4). An obstructive apnea episode is defined as a 10-s pause in respiration associated with ongoing ventilatory effort. Obstructive hypopnea is characterized by a partial decrease in ventilation with fall in oxygen saturation. The apnea– hypopnea index (AHI) is calculated as the average number of apneas and hypopneas per hour of sleep. Diagnosis of OSAS is established when the AHI is per h. The typical presentation of OSAS includes a history of loud snoring, witnessed apnea during sleep, obesity and daytime sleepiness (5,6). However, the clinical features of OSAS in patients with ESRD may differ from this classic presentation. Patients with ESRD were less likely to report snoring, witnessed apnea during sleep, unrefreshing sleep and morning headaches. This atypical presentation of OSAS may lead to under-diagnosis of this important comorbidity in patients with ESRD. OSAS is an independent risk factor for cardiovascular disease, including hypertension, coronary artery disease, congestive heart failure, cardiac arrhythmias and stroke (7–10). OSAS has also been associated with increased overall Correspondence: Mehmet Kanbay, MD, Sag˘l|k Bakanl|g˘|, Istanbul ¨ niversitesi Go¨ztepe Eg˘itim ve Aras t|rma Hastanesi, Medeniyet U _ Kad|ko¨y, Istanbul, Turkey. E-mail: [email protected]
History Received 27 February 2013 Revised 22 March 2013 Accepted 25 March 2013 Published online 16 January 2014
mortality (11). Furthermore, treatment of OSAS with continuous positive airway pressure (CPAP) has been shown to improve endothelial function (12), decrease free radical (13) and inflammatory markers (14,15). Recent evidences suggest that there is a reciprocal relationship between OSAS and chronic kidney disease (CKD): CKD increases the risk of OSAS, while OSAS hasten the progression of CKD. In this review, we aimed to summarize the evidences supporting the complex interrelations between OSAS and development and progression of CKD.
CKD leading to OSAS Each of the OSAS-associated cardiovascular risk factors such as hypertension and diabetes mellitus is also a risk factor for CKD; thus patients with OSAS have a high prevalence of CKD, and conversely patients with CKD exhibit a high incidence of OSAS (16,17) (Figure 1). In a recent study by our group, a significant association between increased severity of OSAS defined by AHI and decreased kidney function (estimated glomerular filtration rate (eGFR)) was found, which remained statistically significant even after adjustment for established kidney disease progression risk factors such as gender, age, hypertension and diabetes (18). Sakaguchi et al. reported that a high prevalence (65%) of OSAS was found in non-dialysis CKD patients; furthermore, approximately one-third of these patients had moderate or severe OSAS (19). This study also demonstrated that decreased GFR was a significant predictor of OSAS. In a cross-sectional study, Sim et al. (20) found an increased risk
Clin Exp Hypertens Downloaded from informahealthcare.com by Nyu Medical Center on 10/12/14 For personal use only.
212
A. Ozkok et al.
of sleep apnea in patients with mild GFR loss. In a recent study, high serum levels of cystatin C were found to be correlated with the severity of OSAS (21). In contrast to the aforementioned reports, in a study performed on 2696 men aged over 65 years, no significant association was found between renal function and sleep disordered breathing (22). However, most of the subjects were generally healthy men with mean serum creatinine levels of 0.99 mg/dl, and only 14.8% had an eGFR560 ml/min per 1.73 m2. The authors suggested that there might be a threshold at which the association between renal function and OSAS could be detected. Most of the studies have found an association between OSAS and CKD, but it is difficult to determine how much of the relationship is associated with hypertension or diabetes even if a statistical correction for demographic data (including hypertension and diabetes) was performed. Of note, in the study by Chou et al., a high prevalence of CKD was still observed in patients with severe OSAS without hypertension or diabetes, and significant correlations were found between the severity of OSAS and renal function impairment (23). In previous studies, uremic toxins, metabolic acidosis, amino-acid metabolism abnormalities and hormone imbalance have been suggested to be associated with the sleep apnea in patients with HD (24–26). In the study performed on 30 patients with HD by Tada et al., metabolic acidosis represented by serum bicarbonate, severity of uremia (blood urea nitrogen and creatinine) and body mass index (BMI) were significantly associated with OSAS index, namely AHI (27). Similarly, Millman et al. (25) showed a correlation between serum creatinine and AHI in patients with HD. OSAS is known to be more prevalent in patients with edematous states, such as heart failure and ESRD when compared to the general population (28–30). In a recent study, a short course of aggressive diuretic treatment in patients with OSAS and diastolic heart failure provided a significant increase in upper airway diameter and also a significant improvement in OSAS severity (31). It may be hypothesized that hypervolemia increases the risk of OSAS. Fluid that has accumulated in the lower extremities may shift into the neck while on the recumbent position during sleep in hypervolemic patients. This fluid shift may cause distension of the veins of the neck and edema of the peripharyngeal soft tissue and eventually upper airway obstruction. In the study by Elias et al., possible role of overnight rostral fluid shift on OSAS was investigated in patients with ESRD (32). The amount of fluid shifted from the legs was related to apnea–hypopnea time. Furthermore, there was a significant association between the overnight change in leg fluid volume and the overnight change in neck circumference. In conclusion, the authors suggested that overnight redistribution of fluid into the neck from the lower extremities during recumbency might play a role in the pathogenesis of OSAS in patients with ESRD. In addition, the upper airway dimensions in patients with CKD were found to be prone to narrowing. Beecroft et al. reported that the pharyngeal cross-sectional area in patients with ESRD was 12% less than that in the control group matched for BMI (33). As described previously, a reduction as small as a 6% in the pharyngeal cross-sectional area translates into a 73% increase in AHI (34).
Clin Exp Hypertens, 2014; 36(4): 211–216
OSAS leading to CKD There are several potential pathophysiological pathways by which OSAS may lead to development and progression of CKD such as hypertension, arterial stiffness, proteinuria, diabetes, obesity, inflammation and endothelial dysfunction that are separately discussed below. OSAS and hypertension OSAS is a well-documented risk factor for hypertension. In a prospective study performed on 709 individuals, a 3-fold higher risk of hypertension was found in those with clinically significant OSAS (35). In this study, also a dose-response relationship between severity of OSAS and hypertension was found. In a study performed on 125 patients with resistant hypertension, two-thirds of the patients had a secondary cause of hypertension, and OSAS was the most common secondary etiology associated with resistant hypertension (36). In the study by Abdel-Kader et al., association of OSAS with resistant hypertension was investigated in ESRD, non-dialysis CKD and non-CKD subjects (37). Resistant hypertension and severe OSAS (AHI430) were significantly more prevalent in patients with advanced kidney disease. Approximately 30% of CKD subjects had resistant hypertension, and 25% of these patients had severe OSAS. In addition, patients with ESRD with severe OSAS were 7-fold more likely to have resistant hypertension. Hypertension is well established to be a major risk factor for the development and progression of CKD (38). Moreover, blood pressure control is shown to decrease the rate of impairment of kidney function (39,40). Associations between sleep quality and blood pressure dipping have been documented in patients with CKD. In a study by Agarwal et al. (41), sleep fragmentation associated with nocturia was related to a blunted nighttime blood pressure decrease in patients with CKD. Since treatment of OSAS with CPAP has been shown to improve blood pressure control (42), it is possible that patients with OSAS with CKD may benefit from CPAP treatment in terms of better control of hypertension and consequently increased renal survival. Increased sympathetic nervous system (SNS) activity is a key mechanism by which OSAS contributes to hypertension. Animal models suggest that chronic hypoxemia due to OSAS induces SNS outflow and subsequently increases vascular resistance and induces activation of the renin–angiotensin– aldosterone system, leading to hypertension (42). Thus, patients with OSAS have increased serum aldosterone concentration, which has been directly linked to glomerulosclerosis, renal fibrosis and progression of CKD (43). In a case-control study of patients with resistant hypertension, OSAS was found to be very common, and AHI correlated with plasma aldosterone levels (44). Aldosterone may contribute to the pathogenesis of OSAS via renal sodium retention that may explain the anti-hypertensive effect of CPAP therapy in patients with resistant hypertension. In a recent study, aldosterone antagonists were shown to improve OSAS in patients with resistant hypertension (45). Although the previous theory suggested that chronic hypoxemia might be the cause of SNS overactivity, more
Sleep apnea and kidney disease
DOI: 10.3109/10641963.2013.804546
213
OSAS
INFLAMMATION OXIDATIVE STRESS
CKD ENDOTHELIAL DYSFUNCTION
Clin Exp Hypertens Downloaded from informahealthcare.com by Nyu Medical Center on 10/12/14 For personal use only.
SYMPATHETIC ACTIVITY
VASCULAR RESISTANCE
DIABETES MELLITUS
RAAS ACTIVATION
HYPERTENSION
OBESITY
Figure 1. Possible mechanisms by which sleep apnea may contribute to chronic kidney disease development and progression. OSAS has been hypothesized to play role in the occurrence of diabetes mellitus and obesity (dashed lines).
recent data concluded that SNS overactivity could cause OSAS, rather than being a consequence. Indeed renal denervation studies revealed a profound reduction in central SNS outflow and blood pressure with consequent improvement in OSAS severity after denervation (46). Thus, SNS overactivity may be the initiating mechanism, leading both to resistant hypertension and OSAS in patients with CKD. One of the most important consequences of OSAS-induced systemic hypertension is the glomerular hyperfiltration, which is considered a precursor of intraglomerular hypertension and progressive renal damage. Several studies have demonstrated that glomerular hyperfiltration in patients with OSAS may be reversed after CPAP therapy (28,47,48). Kinebuchi et al. (49) assessed renal hemodynamics before and after institution of CPAP in patients with OSAS. There was no significant change in GFR, but renal plasma flow increased significantly after CPAP treatment. Filtration fraction decreased significantly after CPAP treatment suggesting that CPAP decreased hyperfiltration. In summary, three mechanisms that potentially link OSAS and resistant hypertension to CKD and CKD progression include the following: hypervolemia, high renin–angotensin– aldosterone levels and SNS overactivation. OSAS and arterial stiffness Arterial stiffness is a well-known consequence of hypertension and directly related to end-organ damage, including CKD. Multiple studies have shown associations between OSAS and arterial stiffness (50–52) and demonstrated that treatment of OSAS by CPAP can decrease arterial stiffness (50). The association between OSAS and arterial stiffness may have potential implications in CKD progression. A recent
report showed that higher arterial stiffness was independently associated with faster kidney function impairment (54). It is hypothesized that increased arterial stiffness can result in microvascular damage and thus cause impaired kidney function. OSAS and proteinuria Proteinuria is a well-known marker of endothelial dysfunction and glomerular hyperfiltration (53) and thus an independent predictor of CKD progression. Urinary albumin–creatinine ratio has been reported to be independently associated with the severity of OSAS (54–56). Faulx et al. (54) performed overnight polysomnography in 496 patients with mild to severe OSAS and found that after adjusting for BMI, severe OSAS (AHI430) was significantly associated with increased urine albumin excretion, independently of GFR and the presence of diabetes or hypertension. Tsioufis et al. (55) compared hypertensive patients with and without OSAS and found that OSAS was associated with increased albuminuria, and the AHI was a significant predictor of albuminuria. However, in two cross-sectional studies, OSAS was not associated with proteinuria after adjustment for BMI (57,58). Thus, although there seems to be an association between OSAS and proteinuria, it is unclear if this is independent of BMI. In a case study, two patients with severe OSAS and proteinuria41 g/d experienced remissions in proteinuria coincided with correction of OSAS and improvement of blood oxygen levels (59). OSAS and glucose intolerance and diabetes Quality and quantity of sleep may have significant roles in glucose regulation (60). Specifically, experimentally
214
A. Ozkok et al.
Clin Exp Hypertens Downloaded from informahealthcare.com by Nyu Medical Center on 10/12/14 For personal use only.
decreased sleep quantity or increased sleep fragmentation have been shown to markedly increase insulin resistance in healthy individuals. In a study by Spiegel et al. (61), healthy subjects were restricted to 4 h of sleep per night for 6 nights, which resulted in increased insulin resistance. In a recent meta-analysis, after controlling for multiple confounders, short sleepers were 28% more likely to develop type 2 diabetes (62). Furthermore, two prospective studies have found that the presence of OSAS independently increases the risk of developing diabetes (60,63). In addition, a dose-response relationship between the severity of OSAS and hemoglobin-A1c levels was also found (63). Multiple studies have suggested that decreased sleep quantity/quality and probably OSAS are important risk factors for diabetes which is the most common cause of ESRD.
Clin Exp Hypertens, 2014; 36(4): 211–216
Treatment of OSAS in CKD – dialysis dose and control of hypervolemia Intensive dialysis techniques such as nocturnal HD or cyclerassisted peritoneal dialysis (PD) have been reported to improve OSAS severity, which suggested that the control of hypervolemia and the dose of dialysis are important factors for OSAS (78–80). A significant improvement in OSAS has been shown in patients who were converted from conventional HD to nocturnal HD (6 times/week) (78). In parallel to this study, patients who were converted from conventional continuous ambulatory PD to automated nocturnal PD had improvements in their OSAS severity (79). Furthermore, Tang et al. (80) showed that conversion from nocturnal PD to continuous PD was associated with a decrease in upper airway size and worsening of sleep apnea. Sleep apnea–hypopnea syndrome was also observed to improve after renal transplantation (81).
OSAS and obesity There is increasing evidence that obesity is an independent risk factor for CKD (64,65). In several studies, short sleep was suggested to be associated with increased energy intake and elevated BMI (66,67). By impairing sleep quality and quantity, OSAS may induce obesity and increase the risk of obesity-related diseases such as diabetes, hypertension and eventually CKD. Inflammation and endothelial dysfunction OSAS-induced nocturnal hypoxemia is associated with endothelial damage and increased inflammation, which has been represented by high serum levels of C-reactive protein, interleukin-6 and tumor necrosis factor-a in patients with OSAS (68–71). In the same line, OSAS significantly increases reactive oxygen species and oxidative stress markers (70). Moreover, it was shown that vascular endothelial growth factor levels, which may have adverse effects on the progression of CKD, were significantly high in OSAS (72). Endothelial dysfunction, increased inflammation and oxidative stress observed in patients with OSAS suggest the possibility that recurrent hypoxia together with ischemia–reperfusion injury may lead to development and progression of CKD in patients with OSAS (73).
Treatment of OSAS in CKD – CPAP OSAS can be treated effectively with CPAP, which delivers compressed air to the patient via a nasal, or facemask, which prevents the collapse of the upper respiratory airways due to the sleep-related pharyngeal hypotonia. CPAP has been shown to reduce nocturnal apneas–hypopneas, day-time somnolence (74) and improve quality of life, hypertension, left ventricular function and cardiovascular prognosis (75). CPAP may also prevent the progression of nephropathy by reducing glomerular hyperfiltration (49) and reduce plasma rennin/angiotensin II levels providing better blood pressure control (76). Plasma brain natriuretic peptide and urinary meta-adrenaline levels have been reported to decrease with CPAP treatment (77).
Conclusion OSAS is more frequently observed in patients with CKD compared to healthy individuals. Because of the strong association between OSAS and CKD, OSAS may be considered to be a ‘‘cardiorenal toxin’’. However, independent casual relationship of OSAS with proteinuria and diabetes mellitus has not been proven yet. Well designed prospective studies are needed to reveal the exact pathogenesis of the OSAS induced proteinuria, diabetes mellitus and progression of CKD. In conclusion, OSAS should be carefully investigated in patients with CKD and treated appropriately to decrease the cardiovascular risk and slow the progression of renal impairment.
Declaration of interest Part of this study was funded by the University of Medicine and Pharmacy Iasi, grants number 1640/01.02.2013 and IDEI – PCE 2011, PN-II-ID-PCE-2011-3-0637. References 1. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 2002;165:1217–39. 2. Young T, Palta M, Dempsey J, et al. The occurrence of sleepdisordered breathing among middle-aged adults. N Engl J Med 1993;328:1230–5. 3. Chuang LP, Hsu SC, Lin SW, et al. Prevalence of snoring and witnessed apnea in Taiwanese adults. Chang Gung Med J 2008;31: 175–81. 4. Kraus MA, Hamburger RJ. Sleep apnea in renal failure. Adv Perit Dial 1997;13:88–92. 5. American Academy of Sleep Medicine. International classification of sleep disorders. Diagnostic and coding manual American Academy of Sleep Medicine. 2nd ed. Westchester (IL): American Academy of Sleep Medicine; 2005. 6. Guilleminault C, Bassiri A. Clinical features and evaluation of obstructive sleep apnea-hypopnea syndrome and the upper airway resistance syndrome. In: Kryger MH, Roth T, Dement WC, eds. Principles and practices of sleep medicine. Philadelphia (PA): Elsevier; 2005:1043–52. 7. Weiss JW, Launois SH, Anand A, Garpestad E. Cardiovascular morbidity in obstructive sleep apnea. Prog Cardiovasc Dis 1999;41: 367–76.
Clin Exp Hypertens Downloaded from informahealthcare.com by Nyu Medical Center on 10/12/14 For personal use only.
DOI: 10.3109/10641963.2013.804546
8. Yang WS, Lee WJ, Funahashi T, et al. Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin. J Clin Endocrinol Metab 2001;86:3815–19. 9. Peker Y, Kraiczi H, Hedner J, et al. An independent association between obstructive sleep apnoea and coronary artery disease. Eur Respir J 1999;14:179–84. 10. Yaggi HK, Concato J, Kernan WN, et al. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005;353:2034–41. 11. He J, Kryger MH, Zorick FJ, et al. Mortality and apnea index in obstructive sleep apnea. Experience in 385 male patients. Chest 1988;94:9–14. 12. Lattimore JL, Wilcox I, Skilton M, et al. Treatment of obstructive sleep apnoea leads to improved microvascular endothelial function in the systemic circulation. Thorax 2006;61:491–5. 13. Schulz R, Mahmoudi S, Hattar K, et al. Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Impact of continuous positive airway pressure therapy. Am J Respir Crit Care Med 2000;162:566–70. 14. Yokoe T, Minoguchi K, Matsuo H, et al. Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation 2003;107:1129–34. 15. Phillips BG, Narkiewicz K, Pesek CA, et al. Effects of obstructive sleep apnea on endothelin-1 and blood pressure. J Hypertens 1999; 17:61–6. 16. Iseki K, Tohyama K, Matsumoto T, Nakamura H. High prevalence of chronic kidney disease among patients with sleep related breathing disorder (SRBD). Hypertens Res 2008;31:249–55. 17. Canales MT, Taylor BC, Ishani A, et al. Reduced renal function and sleep-disordered breathing in community-dwelling elderly men. Sleep Med 2008;9:637–45. 18. Kanbay A, Buyukoglan H, Ozdogan N, et al. Obstructive sleep apnea syndrome is related to the progression of chronic kidney disease. Int Urol Nephrol 2012;44:535–9. 19. Sakaguchi Y, Shoji T, Kawabata H, et al. High prevalence of obstructive sleep apnea and its association with renal function among nondialysis chronic kidney disease patients in Japan: a cross-sectional study. Clin J Am Soc Nephrol 2011;6:995–1000. 20. Sim JJ, Rasgon SA, Kujubu DA, et al. Sleep apnea in early and advanced chronic kidney disease: Kaiser Permanente Southern California cohort. Chest 2009;135:710–16. 21. Kato K, Takata Y, Usui Y, et al. Severe obstructive sleep apnea increases cystatin C in clinically latent renal dysfunction. Respir Med 2011;105:643–9. 22. Canales M, Lui LY, Taylor B, et al. Renal function and sleepdisordered breathing in older men. Nephrol Dial Transplant 2008; 23:3908–14. 23. Chou YT, Lee PH, Yang CT, et al. Obstructive sleep apnea: a standalone risk factor for chronic kidney disease. Nephrol Dial Transplant 2011;26:2244–50. 24. Kagawa S, Fukumori T. Sleep apnea syndrome in dialysis patients. Nippon Rinsho 2004;62:411–15. 25. Millman RP, Kimmel PL, Shore ET, Wasserstein AG. Sleep apnea in hemodialysis patients: the lack of testosterone effect on its pathogenesis. Nephron 1985;40:407–10. 26. Fein AM, Niederman MS, Imbriano L, Rosen H. Reversal of sleep apnea in uremia by dialysis. Arch Intern Med 1987;147: 1355–6. 27. Tada T, Kusano KF, Ogawa A, et al. The predictors of central and obstructive sleep apnoea in haemodialysis patients. Nephrol Dial Transplant 2007;22:1190–7. 28. Fletcher EC. Obstructive sleep apnea and the kidney. J Am Soc Nephrol 1993;4:1111–21. 29. Dopp JM, Reichmuth KJ, Morgan BJ. Obstructive sleep apnea and hypertension: mechanisms, evaluation, and management. Curr Hypertens Rep 2007;9:529–34. 30. Sukhija R, Aronow WS, Sandhu R, et al. Prevalence of left ventricular hypertrophy in persons with and without obstructive sleep apnea. Cardiol Rev 2006;14:170–2. 31. Bucca CB, Brussino L, Battisti A, et al. Diuretics in obstructive sleep apnea with diastolic heart failure. Chest 2007; 132:440–6. 32. Elias RM, Bradley TD, Kasai T, et al. Rostral overnight fluid shift in end-stage renal disease: relationship with obstructive sleep apnea. Nephrol Dial Transplant 2012;27:1569–73.
Sleep apnea and kidney disease
215
33. Beecroft JM, Hoffstein V, Pierratos A, et al. Pharyngeal narrowing in end-stage renal disease: implications for obstructive sleep apnea. Eur Respir J 2007;30:965–71. 34. Busetto L, Enzi G, Inelmen EM, et al. Obstructive sleep apnea syndrome in morbid obesity: effects of intragastric balloon. Chest 2005;128:618–23. 35. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378–84. 36. Pisoni R, Ahmed MI, Calhoun DA. Characterization and treatment of resistant hypertension. Curr Cardiol Rep 2009;11: 407–13. 37. Abdel-Kader K, Dohar S, Shah N, et al. Resistant hypertension and obstructive sleep apnea in the setting of kidney disease. J Hypertens 2012;30:960–6. 38. Yu HT. Progression of chronic renal failure. Arch Intern Med 2003; 163:1417–29. 39. Wright Jr JT, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA 2002;288:2421–31. 40. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861–9. 41. Agarwal R, Light RP, Bills JE, Hummel LA. Nocturia, nocturnal activity, and nondipping. Hypertension 2009;54:646–51. 42. Dempsey JA, Veasey SC, Morgan BJ, O’Donnell CP. Pathophysiology of sleep apnea. Physiol Rev 2010;90:47–112. 43. Greene EL, Kren S, Hostetter TH. Role of aldosterone in the remnant kidney model in the rat. J Clin Invest 1996;98:1063–8. 44. Pratt-Ubunama MN, Nishizaka MK, Boedefeld RL, et al. Plasma aldosterone is related to severity of obstructive sleep apnea in subjects with resistant hypertension. Chest 2007;131:453–9. 45. Gaddam K, Pimenta E, Thomas SJ, et al. Spironolactone reduces severity of obstructive sleep apnoea in patients with resistant hypertension: a preliminary report. J Hum Hypertens 2010;24: 532–7. 46. Witkowski A, Prejbisz A, Florczak E, et al. Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea. Hypertension 2011;58:559–65. 47. Narkiewicz K, Montano N, Cogliati C, et al. Altered cardiovascular variability in obstructive sleep apnea. Circulation 1998;98: 1071–7. 48. Krieger J, Imbs JL, Schmidt M, et al. Renal function in patients with obstructive sleep apnea. Effects of nasal continuous positive airway pressure. Arch Intern Med 1988;148:1337–40. 49. Kinebuchi S, Kazama JJ, Satoh M, et al. Short-term use of continuous positive airway pressure ameliorates glomerular hyperfiltration in patients with obstructive sleep apnoea syndrome. Clin Sci (Lond) 2004;107:317–22. 50. Doonan RJ, Scheffler P, Lalli M, et al. Increased arterial stiffness in obstructive sleep apnea: a systematic review. Hypertens Res 2011; 34:23–32. 51. Tsioufis C, Thomopoulos K, Dimitriadis K, et al. The incremental effect of obstructive sleep apnoea syndrome on arterial stiffness in newly diagnosed essential hypertensive subjects. J Hypertens 2007; 25:141–6. 52. Peralta CA, Jacobs Jr DR, Katz R, et al. Association of pulse pressure, arterial elasticity, and endothelial function with kidney function decline among adults with estimated GFR460 mL/min/ 1.73 m2: the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Kidney Dis 2012;59:41–9. 53. Ruggenenti P, Remuzzi G. Time to abandon microalbuminuria? Kidney Int 2006;70:1214–22. 54. Faulx MD, Storfer-Isser A, Kirchner HL, et al. Obstructive sleep apnea is associated with increased urinary albumin excretion. Sleep 2007;30:923–9. 55. Tsioufis C, Thomopoulos C, Dimitriadis K, et al. Association of obstructive sleep apnea with urinary albumin excretion in essential hypertension: a cross-sectional study. Am J Kidney Dis 2008;52: 285–93. 56. Ursavas A, Karadag M, Gullulu M, et al. Low-grade urinary albumin excretion in normotensive/non-diabetic obstructive sleep apnea patients. Sleep Breath 2008;12:217–22.
Clin Exp Hypertens Downloaded from informahealthcare.com by Nyu Medical Center on 10/12/14 For personal use only.
216
A. Ozkok et al.
57. Agrawal V, Vanhecke TE, Rai B, et al. Albuminuria and renal function in obese adults evaluated for obstructive sleep apnea. Nephron Clin Pract 2009;113:c140–7. 58. Casserly LF, Chow N, Ali S, et al. Proteinuria in obstructive sleep apnea. Kidney Int 2001;60:1484–9. 59. Sklar AH, Chaudhary BA. Reversible proteinuria in obstructive sleep apnea syndrome. Arch Intern Med 1988;148:87–9. 60. Knutson KL, Ryden AM, Mander BA, Van Cauter E. Role of sleep duration and quality in the risk and severity of type 2 diabetes mellitus. Arch Intern Med 2006;166:1768–74. 61. Spiegel K, Tasali E, Leproult R, Van Cauter E. Effects of poor and short sleep on glucose metabolism and obesity risk. Nat Rev Endocrinol 2009;5:253–61. 62. Cappuccio FP, D’Elia L, Strazzullo P, Miller MA. Quantity and quality of sleep and incidence of type 2 diabetes: a systematic review and meta-analysis. Diabetes Care 2010;33:414–20. 63. Aronsohn RS, Whitmore H, Van Cauter E, Tasali E. Impact of untreated obstructive sleep apnea on glucose control in type 2 diabetes. Am J Respir Crit Care Med 2010;181:507–13. 64. Kramer H, Luke A, Bidani A, et al. Obesity and prevalent and incident CKD: the Hypertension Detection and Follow-Up Program. Am J Kidney Dis 2005;46:587–94. 65. Hsu CY, McCulloch CE, Iribarren C, et al. Body mass index and risk for end-stage renal disease. Ann Intern Med 2006;144: 21–8. 66. Nedeltcheva AV, Kilkus JM, Imperial J, et al. Sleep curtailment is accompanied by increased intake of calories from snacks. Am J Clin Nutr 2009;89:126–33. 67. St Onge MP, Roberts AL, Chen J, et al. Short sleep duration increases energy intakes but does not change energy expenditure in normal-weight individuals. Am J Clin Nutr 2011;94:410–16. 68. Ryan S, Taylor CT, McNicholas WT. Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation 2005;112:2660–7. 69. Kato M, Roberts-Thomson P, Phillips BG, et al. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation 2000;102: 2607–10.
Clin Exp Hypertens, 2014; 36(4): 211–216
70. Yamauchi M, Nakano H, Maekawa J, et al. Oxidative stress in obstructive sleep apnea. Chest 2005;127:1674–9. 71. Dursunoglu N, Dursunoglu D. Obstructive sleep apnea syndrome, endothelial dysfunction and coronary atherosclerosis. Tuberk Toraks 2005;53:299–306. 72. Schulz R, Hummel C, Heinemann S, et al. Serum levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea and severe nighttime hypoxia. Am J Respir Crit Care Med 2002;165:67–70. 73. Fassett RG, Venuthurupalli SK, Gobe GC, et al. Biomarkers in chronic kidney disease: a review. Kidney Int 2011;80:806–21. 74. Engleman HM, Douglas NJ. Sleep. 4: sleepiness, cognitive function, and quality of life in obstructive sleep apnoea/hypopnoea syndrome. Thorax 2004;59:618–22. 75. Kaneko Y, Floras JS, Usui K, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med 2003;348:1233–41. 76. Saarelainen S, Hasan J, Siitonen S, Seppala E. Effect of nasal CPAP treatment on plasma volume, aldosterone and 24-h blood pressure in obstructive sleep apnoea. J Sleep Res 1996;5:181–5. 77. Kita H, Ohi M, Chin K, et al. The nocturnal secretion of cardiac natriuretic peptides during obstructive sleep apnoea and its response to therapy with nasal continuous positive airway pressure. J Sleep Res 1998;7:199–207. 78. Hanly PJ, Pierratos A. Improvement of sleep apnea in patients with chronic renal failure who undergo nocturnal hemodialysis. N Engl J Med 2001;344:102–7. 79. Tang SC, Lam B, Ku PP, et al. Alleviation of sleep apnea in patients with chronic renal failure by nocturnal cycler-assisted peritoneal dialysis compared with conventional continuous ambulatory peritoneal dialysis. J Am Soc Nephrol 2006;17:2607–16. 80. Tang SC, Lam B, Lai AS, et al. Improvement in sleep apnea during nocturnal peritoneal dialysis is associated with reduced airway congestion and better uremic clearance. Clin J Am Soc Nephrol 2009;4:410–18. 81. 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;34:739–44.
ORIGINAL ARTICLE
Obstructive sleep apnea syndrome and chronic kidney disease: a new cardiorenal risk factor Abdullah Ozkok1, Asiye Kanbay2, Ali Riza Odabas1, Adrian Covic3, and Mehmet Kanbay1 Division of Nephrology, Department of Internal Medicine and 2Department of Pulmonary Medicine, Istanbul Medeniyet University School of Medicine, Istanbul, Turkey, and 3Nephrology Clinic, Dialysis and Renal Transplant Center, ‘C.I. PARHON’ University Hospital, ‘Gr. T. Popa’ University of Medicine and Pharmacy, Iasi, Romania
Clin Exp Hypertens Downloaded from informahealthcare.com by Nyu Medical Center on 10/12/14 For personal use only.
1
Abstract
Keywords
Clinical and experimental studies revealed that sleep apnea might be an insidious risk factor for the progression of kidney disease and development of cardiovascular events by exacerbating well-known risk factors, namely hypertension, type 2 diabetes mellitus and obesity. Furthermore, sleep apnea also has a negative impact on endothelial function. Therefore, sleep apnea might be defined as a new cardiorenal risk factor. In this review, we aimed to summarize the evidences supporting the complex inter-relations between sleep apnea and development and progression of chronic kidney disease.
Chronic kidney disease, hypertension, inflammation, sleep apnea
General considerations Obstructive sleep apnea syndrome (OSAS) is a potentially life-threatening disorder characterized by repeated episodes of apnea–hypopnea due to upper airway obstruction. OSAS is a common disease affecting approximately 5–20% of the general population, but it is generally under-diagnosed (1–3). Frequency of sleep apnea has been reported to be 50–70% in patients with end-stage renal disease (ESRD) (4). An obstructive apnea episode is defined as a 10-s pause in respiration associated with ongoing ventilatory effort. Obstructive hypopnea is characterized by a partial decrease in ventilation with fall in oxygen saturation. The apnea– hypopnea index (AHI) is calculated as the average number of apneas and hypopneas per hour of sleep. Diagnosis of OSAS is established when the AHI is per h. The typical presentation of OSAS includes a history of loud snoring, witnessed apnea during sleep, obesity and daytime sleepiness (5,6). However, the clinical features of OSAS in patients with ESRD may differ from this classic presentation. Patients with ESRD were less likely to report snoring, witnessed apnea during sleep, unrefreshing sleep and morning headaches. This atypical presentation of OSAS may lead to under-diagnosis of this important comorbidity in patients with ESRD. OSAS is an independent risk factor for cardiovascular disease, including hypertension, coronary artery disease, congestive heart failure, cardiac arrhythmias and stroke (7–10). OSAS has also been associated with increased overall Correspondence: Mehmet Kanbay, MD, Sag˘l|k Bakanl|g˘|, Istanbul ¨ niversitesi Go¨ztepe Eg˘itim ve Aras t|rma Hastanesi, Medeniyet U _ Kad|ko¨y, Istanbul, Turkey. E-mail: [email protected]
History Received 27 February 2013 Revised 22 March 2013 Accepted 25 March 2013 Published online 16 January 2014
mortality (11). Furthermore, treatment of OSAS with continuous positive airway pressure (CPAP) has been shown to improve endothelial function (12), decrease free radical (13) and inflammatory markers (14,15). Recent evidences suggest that there is a reciprocal relationship between OSAS and chronic kidney disease (CKD): CKD increases the risk of OSAS, while OSAS hasten the progression of CKD. In this review, we aimed to summarize the evidences supporting the complex interrelations between OSAS and development and progression of CKD.
CKD leading to OSAS Each of the OSAS-associated cardiovascular risk factors such as hypertension and diabetes mellitus is also a risk factor for CKD; thus patients with OSAS have a high prevalence of CKD, and conversely patients with CKD exhibit a high incidence of OSAS (16,17) (Figure 1). In a recent study by our group, a significant association between increased severity of OSAS defined by AHI and decreased kidney function (estimated glomerular filtration rate (eGFR)) was found, which remained statistically significant even after adjustment for established kidney disease progression risk factors such as gender, age, hypertension and diabetes (18). Sakaguchi et al. reported that a high prevalence (65%) of OSAS was found in non-dialysis CKD patients; furthermore, approximately one-third of these patients had moderate or severe OSAS (19). This study also demonstrated that decreased GFR was a significant predictor of OSAS. In a cross-sectional study, Sim et al. (20) found an increased risk
Clin Exp Hypertens Downloaded from informahealthcare.com by Nyu Medical Center on 10/12/14 For personal use only.
212
A. Ozkok et al.
of sleep apnea in patients with mild GFR loss. In a recent study, high serum levels of cystatin C were found to be correlated with the severity of OSAS (21). In contrast to the aforementioned reports, in a study performed on 2696 men aged over 65 years, no significant association was found between renal function and sleep disordered breathing (22). However, most of the subjects were generally healthy men with mean serum creatinine levels of 0.99 mg/dl, and only 14.8% had an eGFR560 ml/min per 1.73 m2. The authors suggested that there might be a threshold at which the association between renal function and OSAS could be detected. Most of the studies have found an association between OSAS and CKD, but it is difficult to determine how much of the relationship is associated with hypertension or diabetes even if a statistical correction for demographic data (including hypertension and diabetes) was performed. Of note, in the study by Chou et al., a high prevalence of CKD was still observed in patients with severe OSAS without hypertension or diabetes, and significant correlations were found between the severity of OSAS and renal function impairment (23). In previous studies, uremic toxins, metabolic acidosis, amino-acid metabolism abnormalities and hormone imbalance have been suggested to be associated with the sleep apnea in patients with HD (24–26). In the study performed on 30 patients with HD by Tada et al., metabolic acidosis represented by serum bicarbonate, severity of uremia (blood urea nitrogen and creatinine) and body mass index (BMI) were significantly associated with OSAS index, namely AHI (27). Similarly, Millman et al. (25) showed a correlation between serum creatinine and AHI in patients with HD. OSAS is known to be more prevalent in patients with edematous states, such as heart failure and ESRD when compared to the general population (28–30). In a recent study, a short course of aggressive diuretic treatment in patients with OSAS and diastolic heart failure provided a significant increase in upper airway diameter and also a significant improvement in OSAS severity (31). It may be hypothesized that hypervolemia increases the risk of OSAS. Fluid that has accumulated in the lower extremities may shift into the neck while on the recumbent position during sleep in hypervolemic patients. This fluid shift may cause distension of the veins of the neck and edema of the peripharyngeal soft tissue and eventually upper airway obstruction. In the study by Elias et al., possible role of overnight rostral fluid shift on OSAS was investigated in patients with ESRD (32). The amount of fluid shifted from the legs was related to apnea–hypopnea time. Furthermore, there was a significant association between the overnight change in leg fluid volume and the overnight change in neck circumference. In conclusion, the authors suggested that overnight redistribution of fluid into the neck from the lower extremities during recumbency might play a role in the pathogenesis of OSAS in patients with ESRD. In addition, the upper airway dimensions in patients with CKD were found to be prone to narrowing. Beecroft et al. reported that the pharyngeal cross-sectional area in patients with ESRD was 12% less than that in the control group matched for BMI (33). As described previously, a reduction as small as a 6% in the pharyngeal cross-sectional area translates into a 73% increase in AHI (34).
Clin Exp Hypertens, 2014; 36(4): 211–216
OSAS leading to CKD There are several potential pathophysiological pathways by which OSAS may lead to development and progression of CKD such as hypertension, arterial stiffness, proteinuria, diabetes, obesity, inflammation and endothelial dysfunction that are separately discussed below. OSAS and hypertension OSAS is a well-documented risk factor for hypertension. In a prospective study performed on 709 individuals, a 3-fold higher risk of hypertension was found in those with clinically significant OSAS (35). In this study, also a dose-response relationship between severity of OSAS and hypertension was found. In a study performed on 125 patients with resistant hypertension, two-thirds of the patients had a secondary cause of hypertension, and OSAS was the most common secondary etiology associated with resistant hypertension (36). In the study by Abdel-Kader et al., association of OSAS with resistant hypertension was investigated in ESRD, non-dialysis CKD and non-CKD subjects (37). Resistant hypertension and severe OSAS (AHI430) were significantly more prevalent in patients with advanced kidney disease. Approximately 30% of CKD subjects had resistant hypertension, and 25% of these patients had severe OSAS. In addition, patients with ESRD with severe OSAS were 7-fold more likely to have resistant hypertension. Hypertension is well established to be a major risk factor for the development and progression of CKD (38). Moreover, blood pressure control is shown to decrease the rate of impairment of kidney function (39,40). Associations between sleep quality and blood pressure dipping have been documented in patients with CKD. In a study by Agarwal et al. (41), sleep fragmentation associated with nocturia was related to a blunted nighttime blood pressure decrease in patients with CKD. Since treatment of OSAS with CPAP has been shown to improve blood pressure control (42), it is possible that patients with OSAS with CKD may benefit from CPAP treatment in terms of better control of hypertension and consequently increased renal survival. Increased sympathetic nervous system (SNS) activity is a key mechanism by which OSAS contributes to hypertension. Animal models suggest that chronic hypoxemia due to OSAS induces SNS outflow and subsequently increases vascular resistance and induces activation of the renin–angiotensin– aldosterone system, leading to hypertension (42). Thus, patients with OSAS have increased serum aldosterone concentration, which has been directly linked to glomerulosclerosis, renal fibrosis and progression of CKD (43). In a case-control study of patients with resistant hypertension, OSAS was found to be very common, and AHI correlated with plasma aldosterone levels (44). Aldosterone may contribute to the pathogenesis of OSAS via renal sodium retention that may explain the anti-hypertensive effect of CPAP therapy in patients with resistant hypertension. In a recent study, aldosterone antagonists were shown to improve OSAS in patients with resistant hypertension (45). Although the previous theory suggested that chronic hypoxemia might be the cause of SNS overactivity, more
Sleep apnea and kidney disease
DOI: 10.3109/10641963.2013.804546
213
OSAS
INFLAMMATION OXIDATIVE STRESS
CKD ENDOTHELIAL DYSFUNCTION
Clin Exp Hypertens Downloaded from informahealthcare.com by Nyu Medical Center on 10/12/14 For personal use only.
SYMPATHETIC ACTIVITY
VASCULAR RESISTANCE
DIABETES MELLITUS
RAAS ACTIVATION
HYPERTENSION
OBESITY
Figure 1. Possible mechanisms by which sleep apnea may contribute to chronic kidney disease development and progression. OSAS has been hypothesized to play role in the occurrence of diabetes mellitus and obesity (dashed lines).
recent data concluded that SNS overactivity could cause OSAS, rather than being a consequence. Indeed renal denervation studies revealed a profound reduction in central SNS outflow and blood pressure with consequent improvement in OSAS severity after denervation (46). Thus, SNS overactivity may be the initiating mechanism, leading both to resistant hypertension and OSAS in patients with CKD. One of the most important consequences of OSAS-induced systemic hypertension is the glomerular hyperfiltration, which is considered a precursor of intraglomerular hypertension and progressive renal damage. Several studies have demonstrated that glomerular hyperfiltration in patients with OSAS may be reversed after CPAP therapy (28,47,48). Kinebuchi et al. (49) assessed renal hemodynamics before and after institution of CPAP in patients with OSAS. There was no significant change in GFR, but renal plasma flow increased significantly after CPAP treatment. Filtration fraction decreased significantly after CPAP treatment suggesting that CPAP decreased hyperfiltration. In summary, three mechanisms that potentially link OSAS and resistant hypertension to CKD and CKD progression include the following: hypervolemia, high renin–angotensin– aldosterone levels and SNS overactivation. OSAS and arterial stiffness Arterial stiffness is a well-known consequence of hypertension and directly related to end-organ damage, including CKD. Multiple studies have shown associations between OSAS and arterial stiffness (50–52) and demonstrated that treatment of OSAS by CPAP can decrease arterial stiffness (50). The association between OSAS and arterial stiffness may have potential implications in CKD progression. A recent
report showed that higher arterial stiffness was independently associated with faster kidney function impairment (54). It is hypothesized that increased arterial stiffness can result in microvascular damage and thus cause impaired kidney function. OSAS and proteinuria Proteinuria is a well-known marker of endothelial dysfunction and glomerular hyperfiltration (53) and thus an independent predictor of CKD progression. Urinary albumin–creatinine ratio has been reported to be independently associated with the severity of OSAS (54–56). Faulx et al. (54) performed overnight polysomnography in 496 patients with mild to severe OSAS and found that after adjusting for BMI, severe OSAS (AHI430) was significantly associated with increased urine albumin excretion, independently of GFR and the presence of diabetes or hypertension. Tsioufis et al. (55) compared hypertensive patients with and without OSAS and found that OSAS was associated with increased albuminuria, and the AHI was a significant predictor of albuminuria. However, in two cross-sectional studies, OSAS was not associated with proteinuria after adjustment for BMI (57,58). Thus, although there seems to be an association between OSAS and proteinuria, it is unclear if this is independent of BMI. In a case study, two patients with severe OSAS and proteinuria41 g/d experienced remissions in proteinuria coincided with correction of OSAS and improvement of blood oxygen levels (59). OSAS and glucose intolerance and diabetes Quality and quantity of sleep may have significant roles in glucose regulation (60). Specifically, experimentally
214
A. Ozkok et al.
Clin Exp Hypertens Downloaded from informahealthcare.com by Nyu Medical Center on 10/12/14 For personal use only.
decreased sleep quantity or increased sleep fragmentation have been shown to markedly increase insulin resistance in healthy individuals. In a study by Spiegel et al. (61), healthy subjects were restricted to 4 h of sleep per night for 6 nights, which resulted in increased insulin resistance. In a recent meta-analysis, after controlling for multiple confounders, short sleepers were 28% more likely to develop type 2 diabetes (62). Furthermore, two prospective studies have found that the presence of OSAS independently increases the risk of developing diabetes (60,63). In addition, a dose-response relationship between the severity of OSAS and hemoglobin-A1c levels was also found (63). Multiple studies have suggested that decreased sleep quantity/quality and probably OSAS are important risk factors for diabetes which is the most common cause of ESRD.
Clin Exp Hypertens, 2014; 36(4): 211–216
Treatment of OSAS in CKD – dialysis dose and control of hypervolemia Intensive dialysis techniques such as nocturnal HD or cyclerassisted peritoneal dialysis (PD) have been reported to improve OSAS severity, which suggested that the control of hypervolemia and the dose of dialysis are important factors for OSAS (78–80). A significant improvement in OSAS has been shown in patients who were converted from conventional HD to nocturnal HD (6 times/week) (78). In parallel to this study, patients who were converted from conventional continuous ambulatory PD to automated nocturnal PD had improvements in their OSAS severity (79). Furthermore, Tang et al. (80) showed that conversion from nocturnal PD to continuous PD was associated with a decrease in upper airway size and worsening of sleep apnea. Sleep apnea–hypopnea syndrome was also observed to improve after renal transplantation (81).
OSAS and obesity There is increasing evidence that obesity is an independent risk factor for CKD (64,65). In several studies, short sleep was suggested to be associated with increased energy intake and elevated BMI (66,67). By impairing sleep quality and quantity, OSAS may induce obesity and increase the risk of obesity-related diseases such as diabetes, hypertension and eventually CKD. Inflammation and endothelial dysfunction OSAS-induced nocturnal hypoxemia is associated with endothelial damage and increased inflammation, which has been represented by high serum levels of C-reactive protein, interleukin-6 and tumor necrosis factor-a in patients with OSAS (68–71). In the same line, OSAS significantly increases reactive oxygen species and oxidative stress markers (70). Moreover, it was shown that vascular endothelial growth factor levels, which may have adverse effects on the progression of CKD, were significantly high in OSAS (72). Endothelial dysfunction, increased inflammation and oxidative stress observed in patients with OSAS suggest the possibility that recurrent hypoxia together with ischemia–reperfusion injury may lead to development and progression of CKD in patients with OSAS (73).
Treatment of OSAS in CKD – CPAP OSAS can be treated effectively with CPAP, which delivers compressed air to the patient via a nasal, or facemask, which prevents the collapse of the upper respiratory airways due to the sleep-related pharyngeal hypotonia. CPAP has been shown to reduce nocturnal apneas–hypopneas, day-time somnolence (74) and improve quality of life, hypertension, left ventricular function and cardiovascular prognosis (75). CPAP may also prevent the progression of nephropathy by reducing glomerular hyperfiltration (49) and reduce plasma rennin/angiotensin II levels providing better blood pressure control (76). Plasma brain natriuretic peptide and urinary meta-adrenaline levels have been reported to decrease with CPAP treatment (77).
Conclusion OSAS is more frequently observed in patients with CKD compared to healthy individuals. Because of the strong association between OSAS and CKD, OSAS may be considered to be a ‘‘cardiorenal toxin’’. However, independent casual relationship of OSAS with proteinuria and diabetes mellitus has not been proven yet. Well designed prospective studies are needed to reveal the exact pathogenesis of the OSAS induced proteinuria, diabetes mellitus and progression of CKD. In conclusion, OSAS should be carefully investigated in patients with CKD and treated appropriately to decrease the cardiovascular risk and slow the progression of renal impairment.
Declaration of interest Part of this study was funded by the University of Medicine and Pharmacy Iasi, grants number 1640/01.02.2013 and IDEI – PCE 2011, PN-II-ID-PCE-2011-3-0637. References 1. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 2002;165:1217–39. 2. Young T, Palta M, Dempsey J, et al. The occurrence of sleepdisordered breathing among middle-aged adults. N Engl J Med 1993;328:1230–5. 3. Chuang LP, Hsu SC, Lin SW, et al. Prevalence of snoring and witnessed apnea in Taiwanese adults. Chang Gung Med J 2008;31: 175–81. 4. Kraus MA, Hamburger RJ. Sleep apnea in renal failure. Adv Perit Dial 1997;13:88–92. 5. American Academy of Sleep Medicine. International classification of sleep disorders. Diagnostic and coding manual American Academy of Sleep Medicine. 2nd ed. Westchester (IL): American Academy of Sleep Medicine; 2005. 6. Guilleminault C, Bassiri A. Clinical features and evaluation of obstructive sleep apnea-hypopnea syndrome and the upper airway resistance syndrome. In: Kryger MH, Roth T, Dement WC, eds. Principles and practices of sleep medicine. Philadelphia (PA): Elsevier; 2005:1043–52. 7. Weiss JW, Launois SH, Anand A, Garpestad E. Cardiovascular morbidity in obstructive sleep apnea. Prog Cardiovasc Dis 1999;41: 367–76.
Clin Exp Hypertens Downloaded from informahealthcare.com by Nyu Medical Center on 10/12/14 For personal use only.
DOI: 10.3109/10641963.2013.804546
8. Yang WS, Lee WJ, Funahashi T, et al. Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin. J Clin Endocrinol Metab 2001;86:3815–19. 9. Peker Y, Kraiczi H, Hedner J, et al. An independent association between obstructive sleep apnoea and coronary artery disease. Eur Respir J 1999;14:179–84. 10. Yaggi HK, Concato J, Kernan WN, et al. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005;353:2034–41. 11. He J, Kryger MH, Zorick FJ, et al. Mortality and apnea index in obstructive sleep apnea. Experience in 385 male patients. Chest 1988;94:9–14. 12. Lattimore JL, Wilcox I, Skilton M, et al. Treatment of obstructive sleep apnoea leads to improved microvascular endothelial function in the systemic circulation. Thorax 2006;61:491–5. 13. Schulz R, Mahmoudi S, Hattar K, et al. Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Impact of continuous positive airway pressure therapy. Am J Respir Crit Care Med 2000;162:566–70. 14. Yokoe T, Minoguchi K, Matsuo H, et al. Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation 2003;107:1129–34. 15. Phillips BG, Narkiewicz K, Pesek CA, et al. Effects of obstructive sleep apnea on endothelin-1 and blood pressure. J Hypertens 1999; 17:61–6. 16. Iseki K, Tohyama K, Matsumoto T, Nakamura H. High prevalence of chronic kidney disease among patients with sleep related breathing disorder (SRBD). Hypertens Res 2008;31:249–55. 17. Canales MT, Taylor BC, Ishani A, et al. Reduced renal function and sleep-disordered breathing in community-dwelling elderly men. Sleep Med 2008;9:637–45. 18. Kanbay A, Buyukoglan H, Ozdogan N, et al. Obstructive sleep apnea syndrome is related to the progression of chronic kidney disease. Int Urol Nephrol 2012;44:535–9. 19. Sakaguchi Y, Shoji T, Kawabata H, et al. High prevalence of obstructive sleep apnea and its association with renal function among nondialysis chronic kidney disease patients in Japan: a cross-sectional study. Clin J Am Soc Nephrol 2011;6:995–1000. 20. Sim JJ, Rasgon SA, Kujubu DA, et al. Sleep apnea in early and advanced chronic kidney disease: Kaiser Permanente Southern California cohort. Chest 2009;135:710–16. 21. Kato K, Takata Y, Usui Y, et al. Severe obstructive sleep apnea increases cystatin C in clinically latent renal dysfunction. Respir Med 2011;105:643–9. 22. Canales M, Lui LY, Taylor B, et al. Renal function and sleepdisordered breathing in older men. Nephrol Dial Transplant 2008; 23:3908–14. 23. Chou YT, Lee PH, Yang CT, et al. Obstructive sleep apnea: a standalone risk factor for chronic kidney disease. Nephrol Dial Transplant 2011;26:2244–50. 24. Kagawa S, Fukumori T. Sleep apnea syndrome in dialysis patients. Nippon Rinsho 2004;62:411–15. 25. Millman RP, Kimmel PL, Shore ET, Wasserstein AG. Sleep apnea in hemodialysis patients: the lack of testosterone effect on its pathogenesis. Nephron 1985;40:407–10. 26. Fein AM, Niederman MS, Imbriano L, Rosen H. Reversal of sleep apnea in uremia by dialysis. Arch Intern Med 1987;147: 1355–6. 27. Tada T, Kusano KF, Ogawa A, et al. The predictors of central and obstructive sleep apnoea in haemodialysis patients. Nephrol Dial Transplant 2007;22:1190–7. 28. Fletcher EC. Obstructive sleep apnea and the kidney. J Am Soc Nephrol 1993;4:1111–21. 29. Dopp JM, Reichmuth KJ, Morgan BJ. Obstructive sleep apnea and hypertension: mechanisms, evaluation, and management. Curr Hypertens Rep 2007;9:529–34. 30. Sukhija R, Aronow WS, Sandhu R, et al. Prevalence of left ventricular hypertrophy in persons with and without obstructive sleep apnea. Cardiol Rev 2006;14:170–2. 31. Bucca CB, Brussino L, Battisti A, et al. Diuretics in obstructive sleep apnea with diastolic heart failure. Chest 2007; 132:440–6. 32. Elias RM, Bradley TD, Kasai T, et al. Rostral overnight fluid shift in end-stage renal disease: relationship with obstructive sleep apnea. Nephrol Dial Transplant 2012;27:1569–73.
Sleep apnea and kidney disease
215
33. Beecroft JM, Hoffstein V, Pierratos A, et al. Pharyngeal narrowing in end-stage renal disease: implications for obstructive sleep apnea. Eur Respir J 2007;30:965–71. 34. Busetto L, Enzi G, Inelmen EM, et al. Obstructive sleep apnea syndrome in morbid obesity: effects of intragastric balloon. Chest 2005;128:618–23. 35. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378–84. 36. Pisoni R, Ahmed MI, Calhoun DA. Characterization and treatment of resistant hypertension. Curr Cardiol Rep 2009;11: 407–13. 37. Abdel-Kader K, Dohar S, Shah N, et al. Resistant hypertension and obstructive sleep apnea in the setting of kidney disease. J Hypertens 2012;30:960–6. 38. Yu HT. Progression of chronic renal failure. Arch Intern Med 2003; 163:1417–29. 39. Wright Jr JT, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA 2002;288:2421–31. 40. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861–9. 41. Agarwal R, Light RP, Bills JE, Hummel LA. Nocturia, nocturnal activity, and nondipping. Hypertension 2009;54:646–51. 42. Dempsey JA, Veasey SC, Morgan BJ, O’Donnell CP. Pathophysiology of sleep apnea. Physiol Rev 2010;90:47–112. 43. Greene EL, Kren S, Hostetter TH. Role of aldosterone in the remnant kidney model in the rat. J Clin Invest 1996;98:1063–8. 44. Pratt-Ubunama MN, Nishizaka MK, Boedefeld RL, et al. Plasma aldosterone is related to severity of obstructive sleep apnea in subjects with resistant hypertension. Chest 2007;131:453–9. 45. Gaddam K, Pimenta E, Thomas SJ, et al. Spironolactone reduces severity of obstructive sleep apnoea in patients with resistant hypertension: a preliminary report. J Hum Hypertens 2010;24: 532–7. 46. Witkowski A, Prejbisz A, Florczak E, et al. Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea. Hypertension 2011;58:559–65. 47. Narkiewicz K, Montano N, Cogliati C, et al. Altered cardiovascular variability in obstructive sleep apnea. Circulation 1998;98: 1071–7. 48. Krieger J, Imbs JL, Schmidt M, et al. Renal function in patients with obstructive sleep apnea. Effects of nasal continuous positive airway pressure. Arch Intern Med 1988;148:1337–40. 49. Kinebuchi S, Kazama JJ, Satoh M, et al. Short-term use of continuous positive airway pressure ameliorates glomerular hyperfiltration in patients with obstructive sleep apnoea syndrome. Clin Sci (Lond) 2004;107:317–22. 50. Doonan RJ, Scheffler P, Lalli M, et al. Increased arterial stiffness in obstructive sleep apnea: a systematic review. Hypertens Res 2011; 34:23–32. 51. Tsioufis C, Thomopoulos K, Dimitriadis K, et al. The incremental effect of obstructive sleep apnoea syndrome on arterial stiffness in newly diagnosed essential hypertensive subjects. J Hypertens 2007; 25:141–6. 52. Peralta CA, Jacobs Jr DR, Katz R, et al. Association of pulse pressure, arterial elasticity, and endothelial function with kidney function decline among adults with estimated GFR460 mL/min/ 1.73 m2: the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Kidney Dis 2012;59:41–9. 53. Ruggenenti P, Remuzzi G. Time to abandon microalbuminuria? Kidney Int 2006;70:1214–22. 54. Faulx MD, Storfer-Isser A, Kirchner HL, et al. Obstructive sleep apnea is associated with increased urinary albumin excretion. Sleep 2007;30:923–9. 55. Tsioufis C, Thomopoulos C, Dimitriadis K, et al. Association of obstructive sleep apnea with urinary albumin excretion in essential hypertension: a cross-sectional study. Am J Kidney Dis 2008;52: 285–93. 56. Ursavas A, Karadag M, Gullulu M, et al. Low-grade urinary albumin excretion in normotensive/non-diabetic obstructive sleep apnea patients. Sleep Breath 2008;12:217–22.
Clin Exp Hypertens Downloaded from informahealthcare.com by Nyu Medical Center on 10/12/14 For personal use only.
216
A. Ozkok et al.
57. Agrawal V, Vanhecke TE, Rai B, et al. Albuminuria and renal function in obese adults evaluated for obstructive sleep apnea. Nephron Clin Pract 2009;113:c140–7. 58. Casserly LF, Chow N, Ali S, et al. Proteinuria in obstructive sleep apnea. Kidney Int 2001;60:1484–9. 59. Sklar AH, Chaudhary BA. Reversible proteinuria in obstructive sleep apnea syndrome. Arch Intern Med 1988;148:87–9. 60. Knutson KL, Ryden AM, Mander BA, Van Cauter E. Role of sleep duration and quality in the risk and severity of type 2 diabetes mellitus. Arch Intern Med 2006;166:1768–74. 61. Spiegel K, Tasali E, Leproult R, Van Cauter E. Effects of poor and short sleep on glucose metabolism and obesity risk. Nat Rev Endocrinol 2009;5:253–61. 62. Cappuccio FP, D’Elia L, Strazzullo P, Miller MA. Quantity and quality of sleep and incidence of type 2 diabetes: a systematic review and meta-analysis. Diabetes Care 2010;33:414–20. 63. Aronsohn RS, Whitmore H, Van Cauter E, Tasali E. Impact of untreated obstructive sleep apnea on glucose control in type 2 diabetes. Am J Respir Crit Care Med 2010;181:507–13. 64. Kramer H, Luke A, Bidani A, et al. Obesity and prevalent and incident CKD: the Hypertension Detection and Follow-Up Program. Am J Kidney Dis 2005;46:587–94. 65. Hsu CY, McCulloch CE, Iribarren C, et al. Body mass index and risk for end-stage renal disease. Ann Intern Med 2006;144: 21–8. 66. Nedeltcheva AV, Kilkus JM, Imperial J, et al. Sleep curtailment is accompanied by increased intake of calories from snacks. Am J Clin Nutr 2009;89:126–33. 67. St Onge MP, Roberts AL, Chen J, et al. Short sleep duration increases energy intakes but does not change energy expenditure in normal-weight individuals. Am J Clin Nutr 2011;94:410–16. 68. Ryan S, Taylor CT, McNicholas WT. Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation 2005;112:2660–7. 69. Kato M, Roberts-Thomson P, Phillips BG, et al. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation 2000;102: 2607–10.
Clin Exp Hypertens, 2014; 36(4): 211–216
70. Yamauchi M, Nakano H, Maekawa J, et al. Oxidative stress in obstructive sleep apnea. Chest 2005;127:1674–9. 71. Dursunoglu N, Dursunoglu D. Obstructive sleep apnea syndrome, endothelial dysfunction and coronary atherosclerosis. Tuberk Toraks 2005;53:299–306. 72. Schulz R, Hummel C, Heinemann S, et al. Serum levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea and severe nighttime hypoxia. Am J Respir Crit Care Med 2002;165:67–70. 73. Fassett RG, Venuthurupalli SK, Gobe GC, et al. Biomarkers in chronic kidney disease: a review. Kidney Int 2011;80:806–21. 74. Engleman HM, Douglas NJ. Sleep. 4: sleepiness, cognitive function, and quality of life in obstructive sleep apnoea/hypopnoea syndrome. Thorax 2004;59:618–22. 75. Kaneko Y, Floras JS, Usui K, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med 2003;348:1233–41. 76. Saarelainen S, Hasan J, Siitonen S, Seppala E. Effect of nasal CPAP treatment on plasma volume, aldosterone and 24-h blood pressure in obstructive sleep apnoea. J Sleep Res 1996;5:181–5. 77. Kita H, Ohi M, Chin K, et al. The nocturnal secretion of cardiac natriuretic peptides during obstructive sleep apnoea and its response to therapy with nasal continuous positive airway pressure. J Sleep Res 1998;7:199–207. 78. Hanly PJ, Pierratos A. Improvement of sleep apnea in patients with chronic renal failure who undergo nocturnal hemodialysis. N Engl J Med 2001;344:102–7. 79. Tang SC, Lam B, Ku PP, et al. Alleviation of sleep apnea in patients with chronic renal failure by nocturnal cycler-assisted peritoneal dialysis compared with conventional continuous ambulatory peritoneal dialysis. J Am Soc Nephrol 2006;17:2607–16. 80. Tang SC, Lam B, Lai AS, et al. Improvement in sleep apnea during nocturnal peritoneal dialysis is associated with reduced airway congestion and better uremic clearance. Clin J Am Soc Nephrol 2009;4:410–18. 81. 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;34:739–44.
