Sleep Disturbances In Chronic Kidney DiseaseⅤ

Bidirectional relationship between sleep apnea and CKD

Extensive evidence supports the concept of a bidirectional relationship between OSA and CKD, as the presence of OSA leads to accelerated decline in renal function, while CKD-particularly renal failure-contributes to the pathogenesis of OSA and CSA.

Click to Cistanche for kidney disease

Sleep apnea is a risk factor for the progression of renal disease.

OSA can lead to accelerated decline in renal function through several direct and indirect mechanisms, including hypoxia, sympathetic nervous system activation, hypertension, inflammation, oxidative stress, and activation of the renin-angiotensin-aldosterone system (RAAS)101–108.

Negative effects of obstructive sleep apnea on renal function. This figure highlights the direct and indirect mechanisms by which intermittent hypoxia associated with obstructive sleep apnea can promote renal injury. For example, intermittent hypoxia can lead to increased free radical production, which can promote oxidative stress, systemic inflammation, and endothelial dysfunction. These effects, in turn, can lead to hypertension. Hypoxia can also directly affect the kidney by activating fibroblasts, leading to increased interstitial fibrosis and apoptosis. Together, these processes ultimately lead to tubulointerstitial injury and chronic kidney disease. GBM, glomerular basement membrane; RAAS, renin–angiotensin–aldosterone system.

The kidney, especially the medulla, is particularly vulnerable to tissue hypoxia101,109. In a mouse model of OSA, intermittent hypoxia induces renal injury with histological damage characterized by glomerular hypertrophy, mesangial matrix expansion, and increased apoptosis110. This evidence is supported by observational data from human studies. A prospective study enrolled 858 patients who underwent diagnostic sleep testing111 and had their estimated glomerular filtration rate (eGFR) measured over a 2-year period; 18% of participants had an eGFR <60 ml/min/1.73 m2, meeting the definition of CKD. After adjustment for sleep apnea severity, age, BMI, and diabetes or heart failure, patients with hypoxia (defined as ≥12% of the recording time with oxygen saturation <90%) had a higher risk of rapid loss of renal function (i.e., a decline in eGFR ≥4 ml/min/1.73 m2/year) (odds ratio (OR) 2.89 (1.25–6.67)). This increased risk remained when modeling reduced renal function at baseline and other recognized risk factors for CKD progression were taken into account. In older adults (age ≥65 years), one study reported that patients with an AHI ≥30 had a higher risk of rapid eGFR decline over an 11-year follow-up period (OR 2.80, 95% CI 1.21–6.44). The increased risk remained significant after adjustment for age, sex, BMI, smoking status, diabetes, hypertension, and history of cardiovascular disease (OR 2.50, 95% CI 1.01–6.20).112 In a study of 161 patients with stage 3–4 CKD, those with a 4% oxygen desaturation index ≥15 (indicating moderate-severe oxygen desaturation) experienced a 3–4-fold faster decline in eGFR compared with those with a 4% oxygen desaturation index <15, after adjustment for confounders including BMI113. Finally, a large cross-sectional study of over 7,000 individuals in the European Sleep Apnea Database cohort found that the lowest nocturnal oxygen saturation was an independent predictor of the presence of CKD, with each unit decrease in lowest oxygen saturation associated with a 2% higher odds of developing CKD114.

OSA can also affect the RAAS due to intermittent hypoxia. In a study of 31 patients with OSA, moderate to severe hypoxia was associated with higher baseline RAAS activity, independent of obesity, and with increased glomerular pressure (indicating a higher risk of renal dysfunction)108. OSA also leads to increased sympathetic nervous system activation and hypertension; this effect can lead to glomerular hyperfiltration, which in turn leads to hypertension and ultimately tubulointerstitial damage, a precursor to CKD109,115,116.

Role of renal failure, hyperlipidemia, and other mechanisms in the pathogenesis of sleep apnea.

As previously mentioned, both types of sleep apnea are very common in patients with renal failure, with an overall prevalence of up to 60%117–119. Although traditional risk factors for sleep apnea still play a role in the pathogenesis of sleep apnea in renal failure, this high prevalence cannot be explained solely by increased age, BMI, or comorbidities, suggesting that renal disease itself contributes to the increased incidence84,120. Pathophysiological mechanisms associated with underlying renal disease that may contribute to sleep apnea include hyperlipidemia, altered chemosensitivity, and uremia-induced neuropathy or myopathy.

Pathophysiological mechanisms that promote sleep apnea in patients with renal failure. Obstructive sleep apnea (OSA) is characterized by recurrent pharyngeal collapse (i.e., complete or partial obstruction of the upper airway) during sleep. In renal failure, hyperlipidemia leads to increased lateral flow of fluid from the internal jugular vein to the upper airway and edema of the upper airway mucosa, resulting in upper airway collapse and increased OSA. Central sleep apnea (CSA) is characterized by a lack of respiratory drive during sleep (i.e., complete or partial reduction in the output of brainstem respiratory signals). In CSA, the upper airway remains patent. Hyperlipidemia associated with renal failure can also lead to pulmonary congestion, similar to heart failure, another condition common in CSA. This congestion leads to changes in the chemical feedback loop mechanisms of the respiratory center, which in turn triggers a cycle of hyperventilation alternating with central apnea or hypopnea.

Limited studies suggest that uremic neuropathy or myopathy plays a role in the pathogenesis of OSA in renal failure. Uremic neuropathy is common in renal failure and can affect sensory function of the upper airway, leading to increased ulceration. Uremic myopathy increases the fatigability of respiratory muscles and may lead to hypotonia of the upper airway dilator muscles, which increases the risk of upper airway collapse during sleep121-123.

Hypervolemia and fluid overload appear to play a key role in the pathogenesis of OSA and CSA in renal failure as well as in heart failure, a condition also characterized by fluid overload and a high incidence of both types of sleep apnea. Fluid overload in the legs and nocturnal oral fluid shifts lead to fluid accumulation in the neck and chest, which can reduce the cross-sectional area of the upper airway, making it more prone to collapse and thus predisposing individuals to OSA. In addition, pulmonary irritant receptors in the lungs can be triggered by fluid accumulation, which will increase the risk of CSA by promoting cycles of hyperventilation and apnea. In patients with renal failure, the amount of nocturnal oral fluid shifts measured by bioelectrical impedance, as well as internal jugular vein volume and upper airway mucosal water content measured by neck MRI, correlated with the severity of sleep apnea. Hypervolemia may also be involved in the pathogenesis.

OSA occurs not only because of its effect on upper airway collapse but also because it increases ventilatory instability128. Although ventilatory instability and periodic breathing have long been considered pathophysiological mechanisms leading to CSA, especially in patients with heart failure, ventilatory instability may also contribute to the pathogenesis of OSA. Increased ventilatory sensitivity to hypercapnia in patients with renal failure is associated with greater severity of OSA. 129 Furthermore, the transition from CHD to nocturnal hemodialysis (NHD) reduces ventilatory sensitivity, which is associated with reduced OSA severity. 130 The mechanisms underlying these changes have not been elucidated but may include a reduction in lung fluid volume and/or improvement in metabolic acidosis.

Observational findings support the role of hyperlipidemia in the pathogenesis of sleep apnea. In a cross-sectional study of CKD patients not receiving dialysis and with a BMI of 24 ± 3.9 kg/m2 (ie, eGFR < 60 ml/min/1.73 m2), patients with severe OSA had significantly higher brain natriuretic peptide (BNP) levels and cardiothoracic ratio than those without OSA and were independent predictors of OSA severity, whereas cardiac systolic function was not. 131 In patients with renal failure treated for CHD, those with moderate to severe sleep apnea had greater total extracellular fluid volume than those with mild or no sleep apnea. 78 Furthermore, in multivariate analysis including BMI, total extracellular fluid volume was the only factor that was independently and directly associated with sleep apnea severity (r = 0.47, P = 0.002).78 Other studies have shown that interdialytic weight gain > 2 kg and the degree of post-hemodialysis fluid overload are independent predictors of OSA severity in patients with renal failure receiving CHD99,132.

How Does Cistanche Treat Kidney Disease?

Cistanche is a traditional Chinese herbal medicine used for centuries to treat various health conditions, including kidney disease. It is derived from the dried stems of Cistanche deserticola, a plant native to the deserts of China and Mongolia. The main active components of cistanche are phenylethanoid glycosides, echinacoside, and acteoside, which have been found to have beneficial effects on kidney health.

Kidney disease, also known as renal disease, refers to a condition in which the kidneys are not functioning properly. This can result in a buildup of waste products and toxins in the body, leading to various symptoms and complications. Cistanche may help treat kidney disease ase through several mechanisms.

Firstly, cistanche has been found to have diuretic properties, meaning it can increase urine production and help eliminate waste products from the body. This can help relieve the burden on the kidneys and prevent the buildup of toxins. By promoting diuresis, cistanche may also help Reduce high blood pressure, a common complication of kidney disease.

Moreover, cistanche has been shown to have antioxidant effects. Oxidative stress, caused by an imbalance between the production of free radicals and the body's antioxidant defenses, plays a key role in the progression of kidney disease. ies help neutralize free radicals and reduce Oxidative stress, thereby protecting the kidneys from damage. The phenylethanoid glycosides found in cistanche have been particularly effective in scavenging free radicals and inhibiting lipid peroxidation.

Additionally, cistanche has been found to have anti-inflammatory effects. Inflammation is another key factor in the development and progression of kidney disease. Cistanche's anti-inflammatory properties help reduce the production of pro-inflammatory cytokines and inhibit the activation of inflammation mandatory pathways, thus alleviating inflammation in the kidneys.

Furthermore, cistanche has been shown to have immunomodulatory effects. In kidney disease, the immune system can be dysregulated, leading to excessive inflammation and tissue damage. Cistanche helps regulate the immune response by modulating the production and activity of immune cells, such as T cells and macrophages. This immune regulation helps reduce inflammation and prevent further damage to the kidneys.

Moreover, cistanche has been found to improve renal function by promoting the regeneration of renal tubes with cells. Renal tubular epithelial cells play a crucial role in the filtration and reabsorption of waste products and electrolytes. In kidney disease, these cells can be damaged, leading to damaged renal function. Cistanche's ability to promote the regeneration of these cells helps restore proper renal function and improve overall kidney health.

In addition to these direct effects on the kidneys, cistanche has been found to have beneficial effects on other organs and systems in the body. This holistic approach to health is particularly important in kidney disease, as the condition often affects multiple organs and systems. che has been shown to have protective effects on the liver, heart, and blood vessels, which are commonly affected by kidney disease. By promoting the health of these organs, cistanche helps improve overall kidney function and prevent further complications.

In conclusion, cistanche is a traditional Chinese herbal medicine used for centuries to treat kidney disease. Its active components have diuretic, antioxidant, anti-inflammatory, immunomodulatory, and regenerative effects, which help improve renal function and protect the kidneys from further damage. , cistanche has beneficial effects on other organs and systems, making it a holistic approach to treating kidney disease.