| Background:Obstructive sleep apnea hypopnea syndrome (OSAHS) is a pathophysiological phenomenon during sleep and is a manifestation of respiratory abnormalities following the Pickwickian syndrome. Which is characterized by frequent apnea with respiratory drive still exists in and (or) hypopnea which are caused by repetitive complete or partial collapse of the upper airways during sleep, and interfere with gas exchange, effect on sleep architecture and autonomic nerve function of sleep related breathing disorder. The most common symptoms of OSAHS patients include irregular sleep snoring, observational apnea, choking or arousal, nocturia, daytime sleepiness and tiredness under adequate sleep, dry mouth, headache, cognitive decline, these symptoms seriously affects the patient daily life and work, severe cases may lead to traffic accident.The diagnosis of OSAHS is confirmed if the number of obstructive events (apneas+hypopneas) on full-night polysomnography (PSG) is greater than 5/hour in a patient who reports any of the following:the bed partner describing loud snoring, breathing interruptions, waking up breath holding, gasping, choking, unintentional sleep episodes during wakefulness, insomnia, unrefreshing sleep, daytime sleepiness, fatigue. And the OSAHS severity is defined as mild for apnea-hypopnea index (AHI) ≥5 and<15/hr, moderate for AHI≥15 and ≤30/hr, and severe for AHI>30/hr. The 1993 Wisconsin Sleep Cohort Study of Young et al. reported that in a middle-aged population, the prevalence of obstructive sleep apnea hypopnea syndrome was 4% in middle-aged men and 2% in middle-aged women. Perhaps a result of worsening obesity, aging, smoking, drinking and improving technology over time, especially may in Asian countries.Although recurrent upper airway collapse during sleep is the pathological basis of the development of OSAHS, the results from these abnormal respiratory events is more than the local abnormality. Existing research has confirmed that OSAHS is associated with morbidity and mortality of the systemic arterial hypertension, atherosclerosis, coronary heart disease, arrhythmias, congestive heart failure, pulmonary hypertension, pulmonary heart disease, asthma, chronic obstructive pulmonary disease, cerebrovascular accident, Alzheimer’s disease, Parkinson’s disease, type 2 diabetes, hyperlipidemia, gastroesophageal reflux, sexual dysfunction, nocturia, paroxysmal nocturnal hemoglobinuria, secondary erythrocyte disease and tumour. All of these indicate that OSAHS should be considered a systemic disease.The pathogenesis of these comorbid conditions in OSAHS is not completely understood, but is thought to be multifactorial in origin. Proposed mechanisms by which OSAHS predisposes to comorbid conditions include oxidative stress, systemic inflammation, alterations in sympathetic activity and vascular endothelial dysfunction induced by chronic intermittent hypoxemia (CIH), sleep fragmentation, hemodynamic disturbances. And there is increasing evidence report that intermittent hypoxia plays an important role in the pathobiology of comorbid conditions in OSAHS through activation of systemic inflammation, oxidative stress, and vascular endothelial dysfunction.In recent years, the potential impact of OSAHS on the development of chronic kidney disease (CKD) has received increasing attention in the medical literature, which gives rise to the scholars’concerns.The global prevalence of CKD has increased significantly over the past decade, particularly in the older population. More than 10% of adults have CKD, and this figure rises to 20% in those aged >60 years and to 35% in those aged >70 years. Although this phenomenon has been largely attributed to the increasing prevalence of diabetes, hypertension, and obesity, these chronic medical disorders do not fully explain the growing prevalence of CKD. Several studies have demonstrated that stable chronic kidney disease (CKD, defined as an estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73 m2), end-stage renal disease (ESRD) or kidney transplant patients have high incidence of OSAHS, who defined as an apnea-hypopnea index (AHI) more than 5/hr. On the other hand, some other studies have reported the eGFR was significant decrease in patients with OSAHS (AHI>5/hr), and the prevalence of CKD (eGFR< 60 ml/min/1.73 m2) was significantly higher in patients with OSAHS (AHI>5/hr). Furthermore, multivariate regression analysis revealed a significant association between AHI and eGFR. These findings raise the possibility that a bidirectional relationship exists between obstructive sleep apnea hypopnea syndrome and kidney disease. However, the pathogenesis of CKD in OSAHS is remaining speculative.As the main organ of the body, the kidney is involving in the regulation of water, electrolyte and acid-base balance, maintaining the stability of the internal environment. When the severe renal dysfunction caused by various causes, there will be a variety of metabolites, drugs and toxins accumulate in the body, which lead to water, electrolyte and acid-base balance disorders. Conceptually, the kidney can be considered to consist of two functionally distinct but anatomically connected areas, namely the glomerulus and the renal tubule. Due to the anatomical structure of the kidney, although the kidney receives 20% of the total cardiac output, the supply of oxygen to the renal medulla, which receives only 10% of total renal blood low. In addition, the main physiological function of the renal tubule is the reabsorption, secretion, concentration and dilution of the super filtrate to form the urine, which needs to consume a largely oxygen. The imbalance between limited oxygen supply and heavy demand in the renal medulla makes the kidney vulnerable to hypoxic injury. Intrarenal hypoxia has been demonstrated in humans with CKD, and renal tissue hypoxia in experimental animal models causes proteinuria independently of other hemodynamic or biochemical changes, these findings suggested that chronic hypoxia in renal parenchyma was closely related to renal function damage.Therefore, we have reason to suspect that OSAHS may also contribute to the progression of kidney disease either directly through the effects of chronic intermittent hypoxia (CIH) on the kidney, which can increasing oxidative stress, systemic inflammation, alterations in sympathetic activity and induced vascular endothelial dysfunction, or indirectly by increasing arterial hypertension, type 2 diabetes, hyperlipidemia, obesity, all of which have been proposed to reduce kidney function. But most of the current research in this field is to explore patients with OSAHS whether have combine with CKD (eGFR< 60 ml/min/1.73 m2). As is known to all, the occurrence and development of CKD is a chronic pathological physiological process. The K/DOQI suggested that according to the GFR, the pathophysiology of CKD can be divided into 5 stages. The most of current research on this field is used by the patients in 3 or more stage which defined as an estimated glomerular filtration rate of less than 60 ml/min/1.73 m2 as the research objects or the judgment cutoff. However, few studies to explore patients with OSAHS whether have combine with early kidney damage which defined as an estimated glomerular filtration rate of more than 60 ml/min/1.73 m2. CKD is characterized by insidious onset, slow progress, atypical symptoms, and with a chronic progressive pathological process. CKD is believed to start with an initial injury arising from a variety of sources. Once the injury has reached a critical threshold, additional physiologic processes within the kidney, which are largely independent of the initial insult, drive the progression to kidney failure. Which indicate that emphasis has been placed on the need to take preventive measures at an earlier stage. Therefore, to explore the relationship between OSAHS and early renal damage can further understand the effects of OSAHS on renal function, to prevent OSAHS patients develop chronic kidney disease.But most of the studies were based on serum creatinine (sCr) and eGFR as an indicator of kidney damage to assess renal function. Serum creatinine has become the most commonly used biomarker of the renal function, and a serum creatinine based prediction equation has been proposed for eGFR. However, the serum creatinine concentration is affected by extra renal factors, e.g., gender, age, physical activity, diet, and muscle mass. And the kidney has a strong compensatory ability, at an earlier stage of renal damage, the level of serum creatinine may still be in the normal range. When it appears abnormal, most of the patients have been in the middle and late stage, and about 50% of the patients may develop end-stage renal disease. Hence, the measurement of serum creatinine cannot be used as an indicator for early stage of kidney damage. On the other hand, Cystatin C is a nonglycosylated protein from the family of cysteine protease inhibitors, and is independent of gender, age, physical activity, diet or muscle mass. Furthermore, Cystatin C is a low-molecular-weight (13kDa) and positively charged protein, is filtrated by glomeruli, is reabsorbed (>99%) in the proximal convoluted tubules but not secreted, is catabolized, and is not recirculated into blood. Therefore, cystatin C is an "ideal" endogenous biomarker that sensitively reflects the impairment of glomerular filtration function. There is increasing evidence Cystatin C is more sensitive than creatinine for detecting glomerular filtration and could be useful for early diagnosis of CKD.The aim of the present study was to investigate whether OSAHS influences renal function in patients without CKD (eGFR>60ml/min/1.73m2) through serum cystatin C as an indicator of kidney damage to assess renal function, and to further evaluate the relationship and association between severity of OSAHS without CKD and serum cystatin C.Objective:1、To investigate the magnitude of serum cystatin C in severity of OSAHS without CKD(eGFR>60ml/min/1.73m2);2、To evaluate the relationship and association between severity of OSAHS without CKD (eGFR>60ml/min/1.73m2) and serum cystatin C, and to further recognized OSAHS and its effect on early renal function.Methods:1、We enrolled patients (18 to 60 years of age) from January 2012 to June 2015 who presented to our Sleep Medicine Center, complaining of a symptom of snoring, with or without witness episodes of apnea during sleep and daytime sleepiness. None had been previously diagnosed with or treated for OSAHS. Patients had central or mixed sleep apnea hypopnea syndrome, paroxysmal sleep disorders, sleep related motor disorders, CKD, glomerular disease, urinary tract obstruction, autoimmune disease, liver disease, hyperthyroidism, hypothyroidism, cancer, COPD, asthma, interstitial pneumonia, acute inflammatory disease, and any other conditions which could affect cystatin C levels were excluded.2、All participants’ current history, past history, personal history, family history and medications were collected with a unified standard program by physicians in our sleep laboratory. Focus on gender, age, body weight and height, body mass index (BMI), neck circumference and waist circumference.3^ All participants underwent a standard full-night polysomnography in our sleep laboratory at least 7 hours, and all subjects were not to take sleeping pills, and to consume caffeine, drinking, tea that might affect their sleep pattern. The monitoring contents of polysomnography including sleep scoring parameters (bed and up time, the total recording time, total sleep time, sleep latency, REM sleep latency, sleep efficiency), sleep architecture (electroencephalography, electrooculography, electromyography), sleep related apnea or hypopnea events (nasal and oral airflow, thoracic and abdominal movements, pulse oxygen saturation), physical exercise events (periodic limb movement index of sleep, periodic limb movement related arousal), arousal events, electrocardiography, snoring, body position and video of sleep. Sleep stages and related events are mainly based on the guidelines of the American Academy of Sleep Medicine Manual for the Scoring of sleep and Associated Events:apnea was defined as complete cessation of airflow for at least 10 seconds, hypopnea was defined as a reduction in airflow more than 30% for at least 10 seconds associated with oxygen desaturation of 3% or with a arousal event. The apnea-hypopnea index (AHI) was calculated as the total number of respiratory events (apneas plus hypopneas) per hour of sleep. Participants was classified into four categories based on thresholds of AHI-simple snoring as a control subjects, patients with mild, moderate and severe OSAHS was less than 5,5<AHI<15,5<AHI<15, and more than 30 events per hour of sleep, respectively. Patients with OSAHS had been recently diagnosed and were naive to treatment.4、After finishing PSG monitoring in the next day morning, venous blood samples were obtained from the participants in the supine position at rest during fasting to measure the serum levels of the following substances:blood routine, liver and kidney function, thyroid function, blood glucose, blood lipid. Blood pressure was gauged by an automatic sphygmomanometer on the right arm with the participants in a supine position.5、Diagnostic criteria for complications hypertension, diabetes mellitus, and hyperlipidemia are based on the guidelines of prevention and treatment of hypertension in China in 2010, prevention and treatment of type 2 diabetes in China, prevention and treatment of dyslipidemia in Chinese adults in 2007, respectively. For eGFR calculation, the CKD-EPI equation was used:Female:(1)Scr≤0.7mg/dl, eGFR (ml/min/1.73 m2)=144×[Scr (mg/dl)/0.7]-0.329×0.993age; (2)Scr>0.7mg/dl, eGFR (ml/min/1.73 m2)=144x[Scr (mg/dl)/0.7]-1.209×0.993age;,Male:(1)Scr≤0.7mg/dl, eGFR (ml/min/1.73 m2)=141×[Scr (mg/dl)/0.9]-0.411×0.993age; (2)Scr>0.7mg/dl, eGFR (ml/min/1.73 m2)=141×[Scr (mg/dl)/0.9]-1.209×0.993age。6、Statistical analysis was performed by using the SPSS statistical software version 20.0 for Windows. Continuous variables were presented as mean±standard deviation (SD), categorical variables were presented as constituent ratio (n,%). All descriptive data were tested for normal distribution prior to analysis. Descriptive variables in four groups were analyzed by one-way analysis of variance, applying LSD method in multiple comparisons when the variance was homogeneity; when the variance was not homogeneity, we used the robust test of equality of means of Welch, applying Dunnett’s T3 method in multiple comparisons. Categorical variables were compared by the Chi-square test or Fisher’s exact test. The correlations between variables were assessed using Pearson’s correlation or Spearman rank correlation. Multiple linear regression was used to determine the independent predictor of cystatin C. All results were considered statistically significant if p<0.05.Result:1、Baseline demographic and clinical characteristics of patients.A total of 238 patients who naive been diagnosed and treatment with snoring during sleep were enrolled in our study during this period. There were 200 males, accounted for 92%, and 19 females, accounted for 8%. There were 31,39,18 patients with hypertension, diabetes mellitus and mixed hyperlipidemia, and accounted for 13%,16%,8%, respectively. The mean age, BMI, neck circumference, waist circumference, SBP and DBP were 42.95±8.23SD,27.30±3.84SD,40.14±3.63SD, 97.30±9.87SD,130.07±15.51SD,80.62±10.87SD, respectively. Gender, neck circumference, waist circumference, BMI, diabetes among the groups were significant differences (all p<0.05). And there were no differences in age, hypertension and mixed hyperlipidemia between each group (all p>0.05).2、polysomnographic of patients.Based on thresholds of AHI, there were 41,49,56,92 patients in simple snoring group, mild, moderate, and severe OSAHS, respectively. The mean AHI, Average pulse oxygen saturation (ASpO2), Minimum pulse oxygen saturation (MSpO2) were 2.91±1.50SD,95.85±1.36SD,88.51±3.49SD in simple snoring group. The mean AHI, ASpO2, MSpO2 were 9.60±2.57SD,94.86±1.95SD,83.41±4.81SD in mild OSAHS. The mean AHI, ASpO2, MSpO2 were 22.00±4.21SD,94.33±2.85SD,77.95±8.19SD in moderate OSAHS. The mean AHI, ASpO2, MSpO2 were 60.15±17.14SD, 90.35±5.33SD,64.75±10.769SD in severe OSAHS. AHI, ASpO2, MSpO2 among the groups were significant differences (all p<0.05).3、Blood biochemical test results of patients.Serum cystatin C, SOD, WBC and its subtype counts, RBC counts were significantly higher in severe OSAHS than in simple snoring group, mild, moderate OSAHS, with statistical difference (all p<0.05). These variables were no differences between simple snoring group, mild and moderate OSAHS (all p>0.05). And there were no differences in Scr and eGFR between each group (all p>0.05).4、Correlations between cystatin C and anthropometric, polysomnographic, and biological parametersResult of correlations between cystatin C and anthropometric, polysomnographic, and biological parameters were significant and positive correlations between cystatin C and the following variables:gender, BMI, neck circumference, waist circumference, SBP, AHI, WBC (r=0.232, p<0.002; r=0.272, p<0.000; r=0.226; p<0.003;r=0.282, p<0.000; r=0.116, p<0.031; r=0.301, p<0.000; r=0.201, p<0.007, respectively). Cystatin C was negatively correlated with ASpO2, MSpO2, SOD (r=-0.251,p<0.002; r=-0.209, p<0.006; r=-0.245, p<0.003, respectively). No correlation was observed between cystatin C and other parameters.5、Multivariate linear regression analysis between Cys-c and risk factors for renal function of patients.Using cystatin C as dependent variable, multiple linear regression was performed to assess the independent predictor. AHI, gender, SOD was an independent factor of Serum cystatin C after adjustment for confounders (β=0.218, p<0.010;P=0.198, p<0.018;β=-0.217, p<0.009, respectively).Conclusions:1、The present study showed that there were relatively high serum cystatin C levels in severe OSAHS without CKD, when serum creatinine concentration and eGFR were no differences between each group. Our study revealed that serum cystatin C is more sensitive than creatinine for detecting glomerular filtration and could be useful for early diagnosis of kidney damage.2、Serum cystatin C levels showed significant correlations with all of the following variables:gender, BMI, neck circumference, waist circumference, SBP, WBC, SOD, AHI, ASpO2, MSpO2. And AHI was an independent factor of Serum cystatin C after adjustment for confounders, suggested that OSAHS is an independent risk factor for renal function damage, proposed mechanisms might directly through the effects of chronic intermittent hypoxia (CIH) involved in the initiation or exacerbation of early renal function damage.3、SOD, WBC and its subtype counts were significantly higher in severe OSAHS than in simple snoring group, mild, moderate OSAHS, And cystatin C was positively correlated with WBC and its subtype counts, and negatively correlated with SOD, revealed that severe OSAHS patients in chronic subclinical inflammation and oxidative stress state, and mechanism of elevated serum Cys-C concentration may be related to chronic intermittent hypoxia induced oxidative stress and the initiation of the inflammatory cascade. |
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