Patients with end-stage renal disease (ESRD) and nondialysis-dependent chronic kidney disease (CKD) suffer from substantially higher rates of both resistant hypertension and sleep-disordered breathing, both of which are contributing factors to increased cardiovascular mortality in these populations. The prevalence of obstructive sleep apnea (OSA) increases with declining renal function , with an estimated prevalence of around 50% in patients with ESRD , which is substantially higher than that in the general population. In this issue of the Journal of Hypertension, Abdel-Kader et al. report an observational study that demonstrates a significant association between resistant hypertension and OSA in patients with ESRD. Resistant hypertension was significantly associated with severe OSA in ESRD (odds ratio 7.1), but no significant association was found between the two disorders in CKD patients not on dialysis, or controls without kidney disease.
The connection between hypertension and OSA in the general population has been well described. Patients with OSA are at significantly increased risk of developing hypertension, and the severity of OSA correlates with the level of blood pressure (BP) . The association is even more robust among patients with resistant hypertension and those with severe OSA. In a recent study of 125 consecutive patients with resistant hypertension, nearly two-thirds of the patients had a secondary cause of hypertension, and OSA was by far the most common secondary condition associated with resistant hypertension . Whereas renal parenchymal disease was previously considered the most common identifiable factor associated with resistant hypertension, this study showed that 64% of patients with resistant hypertension had OSA, whereas the prevalence of renal parenchymal disease was 1.6%.
Less is known about the potential relationship between resistant hypertension and OSA in patients with renal disease. As the authors note, it may not be appropriate to extrapolate the findings from the general population in patients with kidney disease, in which the characteristics and pathophysiology of OSA may be different. For instance, ESRD patients with OSA are less likely to report snoring, witnessed apnea during sleep, and morning headaches, which are common clinical features of OSA in the general population . In addition, higher BMI and male sex are not consistently associated with OSA in patients with ESRD . Further, there may be features specific to patients with renal failure, including uremic toxins, metabolic acidosis, inflammation, and volume overload, that predispose to sleep-disordered breathing in ESRD and may be less applicable to the general population . The current study suggests that there is an association between resistant hypertension and OSA in ESRD patients, as there is in the general population, which is an interesting finding that warrants further investigation.
This cross-sectional study does not establish causation or illuminate on mechanisms that may link OSA and resistant hypertension in ESRD. We may speculate that one condition predisposes and contributes to the pathophysiology of the other (i.e. OSA leads to resistant hypertension or resistant hypertension leads to OSA), or a common pathophysiologic mechanism predisposes to both conditions. Three mechanisms that potentially link OSA and resistant hypertension in ESRD include the following: volume excess; aldosterone; and sympathetic nervous system (SNS) overactivation. OSA is characterized by arousals from sleep and transient nocturnal hypoxemia that lead to vasoconstriction, activation of the renin–angiotensin system, and increased renal sodium retention, which contributes to volume overload, an important cause of drug-resistant hypertension in patients with renal failure . In addition, volume overload itself is a major feature of both resistant hypertension and OSA and may contribute to the pathogenesis of OSA due to redistribution of fluid from the legs to the neck and chest in the recumbent position, which in turn leads to increased peripharyngeal edema and upper airway resistance . Friedman et al. found that the severity of OSA was strongly related to the amount of leg fluid volume displaced overnight, and in a separate study, such nocturnal rostral fluid shifts correlated with the severity of OSA in patients with ESRD . Furthermore, greater removal of fluid with dialysis led to improvement in OSA in patients with ESRD . Aldosterone excess likely plays a role in resistant hypertension, OSA, and volume overload in patients with kidney disease. Excess aldosterone is a common feature of drug-resistant hypertension and has been found to correlate with the severity of OSA in patients with resistant hypertension . Aldosterone, in turn, may contribute to the pathogenesis of OSA via fluid retention and may explain the variability in BP-lowering effect of continuous positive airway pressure (CPAP) therapy in patients with resistant hypertension.
Finally, SNS overactivation is likely a key mechanism by which OSA contributes to hypertension, as well as the preexisting abnormality that leads to both resistant hypertension and OSA in patients with ESRD. Multiple studies have shown that muscle sympathetic nerve activity (MSNA) is chronically elevated in patients with OSA [12–14] and is improved with nocturnal CPAP . The mechanisms by which OSA leads to chronic SNS overactivation are unclear, but may include chronic activation of sympatho-excitatory peripheral chemoreceptors induced by chronic intermittent hypoxemia [14,16]. When chemoreceptors were deactivated by administration of 100% oxygen, MSNA and BP decreased in patients with OSA, but not in controls, suggesting tonic chemoreflex activation of SNS outflow in OSA. SNS overactivity, in turn, contributes to resistant hypertension via vasoconstriction, activation of the renin–angiotensin system, volume retention, endothelial dysfunction, oxidative stress, and vascular stiffening. Although the prevailing theory had been that chronic intermittent hypoxemia causes sustained increases in SNS activity, newer evidence is emerging that SNS overactivity itself may be a cause of OSA, rather than a consequence. Renal denervation therapy, in which both afferent and efferent renal nerves are disrupted, is accompanied by a profound reduction in central SNS outflow and was found to result in BP reduction and improvement in OSA severity in patients with resistant hypertension and OSA . ESRD and CKD patients have chronically elevated SNS activity at baseline due to multiple mechanisms, including afferent renal nerve activation within the diseased kidneys, which increase cardiovascular risk and contribute to resistant hypertension in these patients [18,19]. Thus, SNS overactivity may be the initiating mechanism that perpetuates both resistant hypertension and OSA in patients with renal failure.
One puzzling aspect of the current study is the lack of association of resistant hypertension and OSA in CKD patients and controls, which was most likely due to small sample size. Whether these associations exist in larger studies, and whether interventions to improve SNS activity or volume status improve resistant hypertension and OSA in patients with kidney disease, remains to be tested.
J.P. is supported by NIH grant K23HL098744, Amgen Nephrology Junior Faculty Award, and the Atlanta Research and Education Foundation.
Conflicts of interest
There are no conflicts of interest.
1. Nicholl DM, Ahmed SB, Loewen AH, Hemmelgarn BR, Sola DY, Beecroft JM, et al.
Declining kidney function increases the prevalence of sleep apnea and nocturnal hypoxia. Chest
2012 [Epub ahead of print].
2. Dudenbostel T, Calhoun DA. Resistant hypertension, obstructive sleep apnoea and aldosterone. J Hum Hypertens
2011 [Epub ahead of print].
3. Abdel-Kader K, Dohar S, Shah N, Jambh M, Reis SE, Strollo P, et al.
Resistant hypertension and obstructive sleep apnea in the setting of kidney disease. J Hypertens
4. Pedrosa RP, Drager LF, Gonzaga CC, Sousa MG, de Paula LK, Amaro AC, et al. Obstructive sleep apnea: the most common secondary cause of hypertension associated with resistant hypertension. Hypertension
5. Beecroft JM, Pierratos A, Hanly PJ. Clinical presentation of obstructive sleep apnea in patients with end-stage renal disease. J Clin Sleep Med
6. Perl J, Unruh ML, Chan CT. Sleep disorders in end-stage renal disease: ’markers of inadequate dialysis’? Kidney Int
7. Tada T, Kusano KF, Ogawa A, Iwasaki J, Sakuragi S, Kusano I, et al. The predictors of central and obstructive sleep apnoea in haemodialysis patients. Nephrol Dial Transplant
8. Tsioufis C, Kordalis A, Flessas D, Anastasopoulos I, Tsiachris D, Papademetriou V, Stefanadis C. Pathophysiology of resistant hypertension: the role of sympathetic nervous system. Int J Hypertens
9. Friedman O, Bradley TD, Chan CT, Parkes R, Logan AG. Relationship between overnight rostral fluid shift and obstructive sleep apnea in drug-resistant hypertension. Hypertension
10. Elias RM, Bradley TD, Kasai T, Motwani SS, Chan CT. Rostral overnight fluid shift in end-stage renal disease: relationship with obstructive sleep apnea. Nephrol Dial Transplant
2011 [Epub ahead of print].
11. Hanly PJ, Pierratos A. Improvement of sleep apnea in patients with chronic renal failure who undergo nocturnal hemodialysis. N Engl J Med
12. Grassi G, Facchini A, Trevano FQ, Dell’Oro R, Arenare F, Tana F, et al. Obstructive sleep apnea-dependent and -independent adrenergic activation in obesity. Hypertension
13. Narkiewicz K, van de Borne PJ, Cooley RL, Dyken ME, Somers VK. Sympathetic activity in obese subjects with and without obstructive sleep apnea. Circulation
14. Narkiewicz K, van de Borne PJ, Montano N, Dyken ME, Phillips BG, Somers VK. Contribution of tonic chemoreflex activation to sympathetic activity and blood pressure in patients with obstructive sleep apnea. Circulation
15. Narkiewicz K, Kato M, Phillips BG, Pesek CA, Davison DE, Somers VK. Nocturnal continuous positive airway pressure decreases daytime sympathetic traffic in obstructive sleep apnea. Circulation
16. Narkiewicz K, van de Borne PJ, Pesek CA, Dyken ME, Montano N, Somers VK. Selective potentiation of peripheral chemoreflex sensitivity in obstructive sleep apnea. Circulation
17. Witkowski A, Prejbisz A, Florczak E, Kądziela J, Śliwiński P, Bieleń P, 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
18. Campese VM, Kogosov E. Renal afferent denervation prevents hypertension in rats with chronic renal failure. Hypertension
1995; 25 (Pt 2):878–882.
19. Park J, Campese VM, Middlekauff HR. Exercise pressor reflex in humans with end-stage renal disease. Am J Physiol Regul Integr Comp Physiol