The effect of PAP on UACR and metabolic indexes in patients with MS and OSAHS

Due to unhealthy dietary habits, sedentary lifestyles, and irregular work-rest routines, the prevalence of Metabolic Syndrome (MS) in China has seen a steady increase in recent years. According to data from the Chinese Center for Disease Control and Prevention, by 2010, the prevalence of MS among Chinese adults aged over 18 had soared to 33.9%. Shockingly, an estimated 450 million individuals in China suffer from MS [1]. MS represents a cluster of metabolic disorders characterized by the simultaneous onset of obesity, hyperglycemia, dyslipidemia, and hypertension, significantly impacting overall health. It can increase the risk of type 2 diabetes and major cardiovascular events by 2 times and 5 times respectively, and can increase other chronic diseases [2].

Meanwhile, Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) stands out as a prevalent sleep-breathing disorder. During sleep, the upper airway of affected individuals repeatedly collapses, leading to intermittent reductions or cessation of ventilation. This occurrence results in hypoxia, hypercapnia, and sleep arousal. Intermittent hypoxia and sleep rhythm disorders caused by OSAHS can also affect the endocrine system and increase the incidence of type 2 diabetes and MS [3].Alarmingly, China has witnessed a surge in OSAHS cases, with an estimated 1.76 million affected individuals, ranking among the highest globally [4].

Indeed, a robust connection exists between MS and OSAHS, and they mutually influence each other. Studies reveal that approximately 60% of individuals with MS also suffer from OSAHS [5]. Conversely, MS is detected in about 40% of patients diagnosed with OSAHS, with the risk of developing MS being nine times higher in those with OSAHS compared to their non-OSAHS counterparts. Furthermore, the risk of MS escalates with the severity of OSAHS [6, 7]. Both MS and OSAHS are systemic diseases capable of inflicting damage on multiple systems, including the renal system. On one hand, various components of MS such as obesity, hyperglycemia, dyslipidemia, and hypertension, can lead to corresponding renal complications including diabetic nephropathy, hypertensive nephropathy, and obesity-associated glomerulopathy [8]. On the other hand, extensive population studies independently abnormal presence of excess proteins in urine. Simultaneously, individuals with proteinuria exhibit a higher prevalence of sleep apnea [9]. Urinary microalbumin is a sensitive indicator of early renal damage. The gold standard for measuring microalbuminuria is the collection of a 24-hour urine sample, but this process is cumbersome. Additionally, using spot urine collection can be influenced by changes in urine volume and concentration, affecting the measurement of urinary microalbumin. The use of urine albumin-to-creatinine ratio (UACR) can correct for the impact of urine concentration and volume on test results [10]. Research by Gansvoort et al. [11] indicates that there is no significant difference in assessing microalbuminuria between 24-hour urine albumin concentration and UACR. The American Diabetes Association also recommends using UACR for screening and diagnosing microalbuminuria. UACR<30μg/mg is defined as normal, 30≤UACR<300μg/mg as microalbuminuria, and UACR≥300μg/mg as macroalbuminuria. Specifically, Patients with OSAHS often manifest microproteinuria, and their UACR is significantly elevated compared to the general population [12].

Positive Airway Pressure (PAP) stands as the primary treatment for patients with OSAHS. This therapeutic equipment administers a continuous positive pressure airflow, transmitting it into the body to support the patient's airway. By establishing an air scaffold, it effectively prevents the collapse of the airway during the patient's inhalation. The objective is to reduce the Apnea-Hypopnea Index (AHI), ameliorate hypoxia, and alleviate clinical symptoms, such as daytime fatigue and somnolence [13]. Given China’s substantial population, there exists a considerable number of patients grappling with both MS and OSAHS often accompanied by early signs of renal injury. Therefore, investigating the efficacy of PAP in this specific cohort carries immense significance. This study aims to explore the impact of PAP on UACR in patients with MS and OSAHS, delving into its effectiveness in managing MS. The findings are poised to contribute valuable insights and theoretical foundation for the subsequent treatment of individuals contending with both MS and OSAHS.

In this study, a total of 69 patients were included, comprising 25 patients in the PAP group, consisting of 20 males and 5 females, with an average age of 38.0(32.5,54.0) years. The no OSAHS treatment group comprised 44 cases with 30 males and 14 females, and an average age of 36.0(29.0,50.25) years. Prior to treatment, a statistically significant difference in AHI was observed between the two groups (P<0.05), indicating that the AHI in the PAP group was higher than that in the no OSAHS treatment group. However, there were no significant differences in sex, age, basic diseases situation and drug usage between the two groups (P>0.05) (Table 1).

The baseline characteristics of the two study groups were similar (P>0.05). After a three-month follow-up, patients in both groups exhibited significant reductions in BMI, SBP, DBP, WC, NC, VFA, FPG, HbA1c, HOMA-IR, TG, TC, LDL-C, UA, MetS Z-score, U-ALB, and UACR compared to baseline values. However, in the PAP group, patients also showed decrease in FCP, FINS, and hs-CRP, while the no OSAHSA treatment group exhibited a decrease in HDL-C (P₂=0.007) and an increase in Scr (P₂<0.001). A comparison between the two groups revealed that the PAP group had more significant reductions in BMI, WC, NC, VFA, FCP, hs-CRP, and UACR compared to the no OSAHS treatment group (P₃<0.05). Although PAP patients did not show a pronounced improvement in the severity of MS, the reduction in MetS Z-score was greater than that observed in the no OSAHS treatment group (Table 2). In addition, we collected the average AHI value of PAP group after 3 months and the percentage of days of using time ≥ 4 hours through the EncoreAnywhere system. The data showed that the average AHI of 25 patients decreased significantly to 3.10(1.95,4.80) times/hour after PAP treatment (P<0.001), and their average percentage of using PAP ≥ 4 hours per night was 88.9%.

In order to further analyze the influencing factors of reducing UACR, spearman correlation analysis was performed between the change value of UACR and the use of PAP, age, sex and anthropometric indicators before treatment. It was found that the improvement of UACR was positively correlated with the use of PAP (P=0.011), neck circumference (P=0.009), TC (P=0.032) and LDL-C (P=0.013) before treatment (Table 3). The pre-treatment value of an indicator in the group minus the post-treatment value is defined as the difference between the treatment indicators, and the letter d is added to the front to distinguish (e.g., dBMI=pre-treatment BMI-post-treatment BMI). In the combined analysis of the two groups, it showed that the improvement of UACR was also positively correlated with dBMI, dNC, dVFA, dHbA1c, dFINS, dHOMA-IR and dhs-CRP (P<0.05).

With dUACR as the dependent variable and the indexes related to dUACR as the independent variables, the linear regression analysis was included respectively. Fig. 2 shows that there were positive correlations of dUACR with dBMI (P=0.048, r=0.239), dVFA (P=0.026, r=0.267), and dHOMA-IR (P=0.043, r =0.245)

Furthermore, multiple linear regression analysis (step by step method) was performed with dUACR as the dependent variable and dBMI, dNC, dVFA, dHbA1C, dFINS, dHOMA-IR and dhs-CRP as independent variables. The results showed that there was a positive linear correlation between dVFA (B=0.537), dHOMA-IR (B=1.000). Besides, dVFA and dHOMA-IR were independent factors affecting dUACR (P<0.05) (Table 4).

The presence of a minimal amount of protein in urine, known as microalbuminuria, signifies an early indication of kidney disease and is often considered a marker of endothelial dysfunction. OSAHS not only contributes to proteinuria, but also correlates with the disease’s severity and the extent of urinary protein excretion. Faulx et al. [17] investigated the urinary protein excretion rates among 496 patients across varying degrees of OSAHS. Their findings revealed a positive correlation between AHI and UACR. Remarkably, this correlation persisted even after excluding subjects with renal insufficiency. Another study compared UACR levels between OSAHS patients and individuals with simple snoring. It was found that OSAHS can induce microalbuminuria, and the severity of this condition correlates with the extent of hypoxemia experienced by the patients [18]. A meta-analysis confirmed an associated between OSAHS and heightened levels of proteinuria alongside reduced eGFR [19]. In the analysis conducted by Liu et al. [12] examining the link between OSAHS and early renal damage, results demonstrated a significant reduction in eGFR among OSAHS patients compared to healthy individuals. This reduction was notably more pronounced in patients with concurrent hypertension and/or diabetes. The above results underscore the detrimental impact of OSHAS on renal function, leading to proteinuria and decreased eGFR. Moreover, individuals affected by both OSAHS and MS exhibit more severe renal impairment compared to those solely diagnosed with OSAHS. Research on the renal damage associated with MS and OSAHS has been primarily limited to exploring either one of the conditions independently. However, considering the interrelated nature of MS and OSAHS, their combined influence likely exacerbates the likelihood of microalbuminuria occurring during the early stage of the disease.

Spearman correlation analysis was conducted to examine the relationship between the decrease in UACR, the use of PAP, and various baseline patients’ data. The results revealed a positive correlation between the reduction in UACR and the use of PAP, as well as baseline parameters such as NC, TC, LDL-C, AHI before treatment. Patients with more severe OSAHS, higher blood lipids and greater NC before intervention, especially those using PAP, exhibited more pronounced reduction in UACR. which suggested that these patients can achieve better benefits in reducing urinary protein. The potential causes of the observed decrease in UACR after treatment were further analyzed. The results indicated a positive correlation between the reduction in UACR and decreases in BMI, NC, VFA, HbA1c, FINS, HOMA-IR and hs-CRP. This suggested that weight loss, reduction in NC, lower HbA1c levels, improved HOMA-IR, and a decrease in microinflammatory state may contribute to the decrease in UACR. Further linear regression analysis with UACR decline value as the dependent variable showed that the decrease of BMI, VFA, FINS, HOMA-IR were positively linearly correlated with UACR decline. Multiple linear regression analysis identified HOMA-IR and VFA decline as independent factors influencing the reduction in UACR.

In addition, in the comparison of the difference between the two groups before and after treatment, the PAP group exhibited a more significant decrease in WC, NC, VFA, FCP and hs-CRP compared to the no OSAHS treatment group. Obesity, heightened visceral fat, and insulin resistance are closely related, and these factors have been linked to the onset of proteinuria. Intermittent hypoxemia resulting from OSAHS can exacerbate stress and activate inflammatory pathways, ultimately leading to endothelial dysfunction and proteinuria. In summary, this study suggested that the mechanism by which PAP reduced urinary protein may be associated with mitigating chronic low-grade inflammation induced by hypoxia in the body. This reduction was accompanied by a decrease in body weight, visceral fat, and an improvement in insulin resistance. Notably, the study underscored the potential importance of reducing visceral fat and improving insulin resistance in the overall efficacy of PAP treatment in alleviating proteinuria.

In alignment with the finding of our study, a multicenter investigation led by Zamarron et al. [20] found that a 52-week course of continuous positive airway pressure (CPAP) treatment was linked to a notable reduction in UACR and improvement in insulin resistance among patients. Yasar et al. [21] showed that even a short-term, one-month CPAP treatment could significantly decrease the urinary albumin excretion rate and UACR. Another study by Daskalopoulou et al. [22] observed that CPAP could reduce sympathetic nerve activity and alleviate proteinuria in OSAHS patients, with this effect persisting for a duration of three months. A meta-analysis further supported these findings, indicating a significant reduction in UACR in patients with OSAHS treated with CPAP [23]. In our investigation focusing on microalbuminuria in MS patients with OSAHS, PAP treatment emerged as a significant factor in reducing UACR. Correlation analysis underscored the relationship between the use of PAP and the decrease in UACR. However, multiple linear regression did not show PAP as an independent factor in reducing UACR. This limitation may be attributed to the study’s small sample size, variations in baseline medication regimens, and other confounding factors. It was crucial to note that while PAP was primary intervention for OSAHS, it may not be the exclusive or paramount treatment for reducing proteinuria in clinical practice. Despite these limitations, this study provided a foundation basis for further research in this area.

Prior researches has consistently demonstrated a substantial association between OSAHS and MS, revealing abnormalities in lipid metabolism [24], the induction of refractory hypertension [25], and an elevated risk of type 2 diabetes [26, 27]. Additionally, OSAHS can exacerbated the severity of MS, although greater physical activity may help mitigate this risk [28]. PAP treatment emerges as a promising intervention, enhancing insulin resistance, glucose metabolism and lowering blood pressure by addressing nocturnal intermittent hypoxia, reducing oxidative stress, and modulating the sympathetic nervous system, among other mechanisms [29, 30]. Various Studies indicate that CPAP treatment not only reduces blood pressure but also ameliorates endothelial dysfunction [31] and atherosclerosis [32]. The impact on lipid metabolism, however, varies across studies. Simon et al. [33] reported a significant reduction in TC and LDL-C with CPAP, while another study showed an increase in HDL-C [34]. A meta-analysis also obtained similar results, revealing decreased TC and TG, increased HDL-C, but no significant effect on LDL-C [35]. In the context of our study, post-treatment analysis revealed that levels of FCP, FINS and HOMA-IR in the PAP group were significantly lower than those in the no OSAHS teatment group (P< 0.05)., which suggested that the PAP group exhibited superior blood glucose control, with a more pronounced improvement in insulin resistance. Although there was no significant difference in the improvement of blood pressure, blood lipid profiles and MS severity between the two groups, the reduction in these indicators within the PAP group was greater than that observed in the no OSAHS treatment group. This implied that while PAP may not exert a conspicuous effect on improving MS itself, it dose contributed significantly to improve associated metabolism.

PAP treatment can reduce UACR in patients with MS and OSAHS, and has the effect of improving metabolic disorders. The decrease of UACR in patients may be related to the decrease of visceral fat and the improvement of insulin resistance.