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Association between elevated cystatin C levels and obstructive sleep apnea hypopnea syndrome: a systematic review and updated meta-analysis

BMC Pulmonary Medicine volume 25, Article number: 56 (2025) Cite this article

Abstract

Objective

This study seeks to elucidate variances in cystatin C levels between patients with Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS) and controls while also assessing the impact of cystatin C on cardiovascular and cerebrovascular complications in patients with OSAHS. Furthermore, the benefits of surgery or continuous positive airway pressure (CPAP) treatment in reducing cystatin C levels in patients with OSAHS were explored.

Methods

A thorough search was undertaken across various medical databases, namely PubMed, CNKI, EMBASE, Web of Science, and WanFang, until October 1, 2024, to determine published articles pertinent to OSAHS. The present research conducted a comprehensive review of the literature concerning cystatin C levels in both patients with OSAHS and controls, variations in cystatin C levels pre-and post-surgery/CPAP treatment, the Pearson/Spearman correlation coefficients between cystatin C levels and sleep monitoring indices, and the hazard ratio (HR) associated with cystatin C levels concerning the onset of cardiovascular and cerebrovascular diseases among patients with OSAHS. Meta-analyses were executed utilizing standardized mean difference (SMD) and correlation coefficients (COR) as effect variables. A fixed-effect model was utilized in cases where heterogeneity was not significant (I2 < 50%). Otherwise, a random-effect model was employed. Statistical analysis was executed utilizing STATA 11.0, GraphPad Prism 8, and R 4.1.3.

Results

Forty articles were included in the final analysis. The serum/plasma cystatin C levels in the OSAHS group were significantly increased relative to the controls (SMD = 0.65, 95%CI: 0.50–0.79, P < 0.001). Subgroup analysis considering mean body mass index (BMI), mean age, ethnicity, and study design type consistently showed significantly elevated serum/plasma cystatin C levels in the OSAHS category relative to the controls. CPAP treatment can significantly decrease serum/plasma cystatin C levels in patients with OSAHS. Moreover, the increase in cystatin C levels may serve as a risk factor for stroke and MACC in patients with OSAHS. Serum/plasma cystatin C levels exhibited a positive correlation with AHI scores and ODI.

Conclusion

Elevated cystatin C levels in patients with OSAHS may pose a risk for the onset of cardiovascular and cerebrovascular diseases. Furthermore, cystatin C levels could serve as a valuable clinical indicator for evaluating treatment effectiveness and severity of OSAHS.

Clinical trial number

Not applicable.

Peer Review reports

Introduction

Obstructive sleep apnea hypopnea syndrome (OSAHS) is a sleep-breathing disorder marked by recurrent upper airway obstruction [1]. Intermittent hypoxemia caused by frequent apnea and hypopnea during sleep in patients with OSAHS is accompanied by a series of systemic pathophysiological changes [2]. Recently, there has been a growing global concern regarding the systemic damage inflicted by OSAHS, particularly its detrimental effects on the cardiovascular system [3, 4]. However, there are fewer studies on renal damage by OSAHS. The kidney, characterized by its high blood flow and perfusion rates, is particularly sensitive to fluctuations in oxygen supply, rendering it susceptible to hypoxic injury [5]. Therefore, the kidney stands as one of the significant target organs damaged in patients with OSAHS [6]. However, due to the atypical clinical manifestations of early renal function injury caused by OSAHS, it is challenging to detect positive results in routine examinations, resulting in misdiagnosis or missed diagnosis.

In clinical practice, the main index for evaluating the overall renal function is the glomerular filtration rate (GFR). Key indicators frequently utilized to estimate GFR include serum urea nitrogen and serum creatinine levels [7]. Despite widespread use in clinical practice, these indicators suffer shortcomings and have a low detection rate for early renal function impairment [8]. In recent years, cystatin C has been recognized as a highly sensitive indicator for evaluating changes in GFR. Canales MT et al. [9] employed cystatin C as an assessment marker for renal impairment, highlighting a higher proportion of sleep apnea in elderly individuals with elevated cystatin C levels. Serum cystatin C has been determined as an earlier and more sensitive biomarker for detecting renal impairment [9]. Emerging investigations have revealed a prominent link between OSAHS and elevated cystatin C levels in patients without chronic kidney disease [10, 11]. However, some studies indicated that elevated cystatin C was only present in patients with severe OSAHS [12, 13]. Therefore, meta-analysis is needed for further evaluation. This study executed a systematic review and meta-analysis of studies reporting serum/plasma cystatin C levels in patients with OSAHS across varying degrees of disease severity. The aim was to explore the link between this biomarker and OSAHS. In addition, differences in cystatin C levels between daytime and nighttime were analyzed. Further, the impact of CPAP on serum cystatin C levels in patients with OSAHS was evaluated. Overall, these findings help to provide new treatment strategies and risk assessment methods for patients with OSAHS.

Methodology

The systematic review protocol for this study has been registered on PROSPERO (https://www.crd.york.ac.uk/PROSPERO) under the number PROSPERO CRD42024519104. The research followed the guidelines detailed in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement, ensuring a systematic evaluation and meta-analysis [14].

Search strategy

Non-English and English articles were searched across various databases, encompassing PubMed, CNKI, EMBASE, Web of Science, and Wanfang. The search utilized keywords such as sleep apnea, obstructive sleep apnea, obstructive sleep apnea hypopnea syndrome, obstructive sleep hypopnea, sleep-disordered breathing, upper airway resistance, cystatin C, cystatin 3 and Cys C, without language limitation. The search period extended from the time of database inception to October 1, 2024. In addition to the computerized search, a manual search was performed on all retrieved articles. Potentially relevant articles were screened per the prespecified inclusion and exclusion criteria. The retrieval strategy is shown in the supplementary Table 1.

Inclusion and exclusion criteria for the literature

Based on the PRISMA guide [15] (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), we used an evidence-based model for framing a PICO question model (PICO: Participants, Intervention, Control, and Outcomes). The inclusion of studies was based on the given criteria.

(1) Participants: Adults or children with OSAHS. The individuals were required to meet the diagnostic criteria for OSAHS as determined by PSG (adults: AHI ≥ 5/h; children: AHI ≥ 1/h) [16]. (2) Intervention: plasma/serum cystatin C levels were carried out by enzyme-linked immunosorbent assay [17] or other accepted methods. (3) Control: healthy participants, of similar age and weight, who have undergone medical and sleep evaluations. (4) Outcomes: plasma/serum cystatin C concentrations.

The exclusion of studies was based on the given criteria:

  1. (1)

    Studies provided sufficient data for meta-analysis. Those lacking sufficient information for data extraction were excluded.

  2. (2)

    Significant differences in baseline sex, age, or body mass index (BMI) were found between the case group and the control group.

  3. (3)

    Abstracts, letters to the editor, animal experiments, and cases were also excluded.

Data extraction

Data from each literature source was systemically extracted by three researchers and consolidated into a standardized spreadsheet format. This spreadsheet encompassed all pertinent data comprising the first author’s name, type of study design, year of publication, sample size, BMI, applicable exposures and interventions, duration of treatment, the adjusted HR, and 95% CI values related to the major adverse cardiovascular event, circadian cystatin C concentrations, and Pearson/Spearman correlation coefficients (CORs) for cystatin C concentrations and PSG indexes.

Literature quality assessment

Owing to the observational nature of the studies meeting the inclusion criteria, the risk of bias in the literature was appraised utilizing the Newcastle-Ottawa Scale (NOS). Articles were assessed for bias at the study level, with bias categorized as low (≥ 8 stars), moderate (5–7 stars), or high (< 5 stars) [14]. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework was used to assess the certainty of evidence independently by Nianying Fu and Xiaotao Tan.

Statistical analysis

The difference in serum/plasma cystatin C levels between the OSAHS group and the control group was evaluated using standardized mean difference (SMD). Following this, the data were stratified into various subgroups based on factors such as BMI, hypertension, sample type, severity, study design, ethnicity, and age, respectively. Subsequently, data from each subgroup were analyzed separately. The difference in serum/plasma cystatin C levels between the pre-CPAP group and the post-CPAP group was also assessed with SMD. The heterogeneity of SMDs was quantified utilizing the I2 test. In instances where heterogeneity was low (I2 < 50), a fixed-effects model was utilized. Conversely, a random-effects model was utilized when heterogeneity was higher. Additionally, the treatment effect across studies was estimated utilizing either the random-effect or fixed-effect model, with the fixed-effect model chosen when it is reasonable to infer that studies are estimating the same underlying treatment effect. A meta-analysis was executed utilizing Pearson CORs to probe the links between the cystatin C concentration and PSG indexes in the patients with OSAHS. This analysis was implemented via the R package “meta”. Fisher’s transformation method was utilized to facilitate direct comparisons across all CORs. The analysis was then conducted utilizing the transformed values as input values before reverting them to CORs [18]. The effect size was then calculated (categorized as small, ≤ 0.3; moderate, 0.3–0.5; and large, > 0.5) and assessed according to Cohen’s criterion. Furthermore, Pearson COR was utilized to investigate the association between the cystatin C levels and PSG indexes (AHI, Oxygen Desaturation Index [ODI], Mean SaO2, Minimum SaO2). In line with this approach, several research reports have referenced the following formula for transforming Pearson’s COR to Spearman’s COR:

$$\:r\hspace{0.17em}=\hspace{0.17em}2\:sin\:\left(rs\frac{\pi\:}{6}\right)$$

Here, r and rs represent the CORs computed utilizing Pearson’s and Spearman’s methods. Egger’s tests were executed to determine publication bias, while the stability of the meta-analysis was assessed through sensitivity analysis. Data analysis was carried out using STATA software (10.0) and R software (4.1.3). P < 0.05 was deemed as a statistically significant Criterion.

Results

Search results

Following the elimination of duplicates, 504 studies were subjected to initial screening. Upon reviewing abstracts and titles, 81 seemingly irrelevant studies were excluded, resulting in a total of 42 remaining studies. Subsequently, after a detailed examination of the full texts of these 42 articles, 11 articles were excluded per the established criteria for the inclusion and exclusion of studies, which comprised 5 reviews, 3 letters to the editor, 2 with insufficient applicable data, and 1 animal experiments. Ultimately, 31 articles fulfilled the criteria and were included in the meta-analysis (Fig. 1).

Fig. 1
figure 1

Flow chart of inclusion criteria in the study

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Characteristics of included studies

Seventeen articles [6, 11,12,13, 19,20,21,22,23,24,25,26,27,28,29,30] compared cystatin C concentrations between patients with OSAHS and controls. Two articles [31, 32] reported circadian cystatin C concentration changes in patients with OSAHS. Four articles [19, 33,34,35] reported cystatin C concentration values before and after CPAP treatment. Two articles [36, 37] reported cystatin C concentration values before and after surgery treatment. Two articles [38, 39] categorized patients with OSAHS into four groups based on quartiles of cystatin C concentrations and evaluated the association of cystatin C concentrations with stroke, major adverse cardiovascular events (MACEs), and all-cause mortality. Additionally, nine articles [11, 12, 20, 22, 33, 35, 39,40,41,42] reported Pearson or Spearman CORs between cystatin C and AHI, ODI, Mean SaO2, and Minimum SaO2. Details regarding authors, publication year, country, sample size, comorbidity (hypertension), sample type, and NOS score of each study are provided in Table 1. The mean age, mean BMI, and Pearson/Spearman correlation coefficients for each study are presented in Table 2. The supplementary Table 2 summaries the certainty of the evidence for outcomes included in the meta-analyses using the GRADE framework. All outcomes were deemed to moderate certainty.

Table 1 Characteristics of included studies
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Table 2 Correlation between sleep indicators and cystatin C level
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Meta-analysis results

Differences in cystatin C concentrations between patients with OSAHS and controls

The I2 value of 82.8% indicated a high heterogeneity among studies. Consequently, a random-effects model was utilized to pool the effect values. The meta-analysis demonstrated that serum/plasma cystatin C levels were higher in the OSAHS group relative to the control group (SMD = 0.66, 95% CI: 0.52–0.81, P < 0.001) (Fig. 2). A moderate certainty of evidence was identified in the GRADE assessment. Due to potential variations in cystatin C test results attributed to sample type, and with only one article available on plasma cystatin C concentrations, separate subgroup analyses were conducted for articles focusing on serum cystatin C concentrations.

Fig. 2
figure 2

Forest plot of SMD and its 95% CI for cystatin C levels in OSAHS patients group compared to the control group in meta-analysis.

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Serum cystatin C

Subgroup analysis-disease severity

Multiple studies included in the analysis provided data on serum cystatin C levels among individuals with varying degrees of OSAHS severity. Consequently, subgroup analyses were carried out as per the classification of OSAHS severity into mild, moderate, or severe. Data regarding serum cystatin C levels in patients with mild OSAHS were obtained from 8 studies. Results indicated elevated cystatin C levels in individuals with mild OSAHS relative to the controls (SMD = 0.45, 95%CI: 0.14–0.75, P = 0.004) (Fig. 3). Moreover, data on serum cystatin C levels were extracted from 11 studies that conducted comparative assessments between individuals with moderate OSAHS and controls. The findings emphasized a significant elevation in serum cystatin C levels among individuals with moderate OSAHS relative to controls (SMD = 0.68, 95%CI: 0.41–0.96, P < 0.001) (Fig. 3). Additionally, 11 studies reported data regarding serum cystatin C levels among individuals with severe OSAHS and controls. The results revealed an elevation in serum cystatin C levels in patients with severe OSAHS relative to controls (SMD = 0.98, 95%CI: 0.63–1.33, P < 0.001) (Fig. 3) (Table 3).

Fig. 3
figure 3

Forest plot of SMD and its 95% CI for cystatin C levels in different severity of patients with OSAHS patients

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Table 3 Subgroup analyses of cystatin C concentrations in OSAHS and controls
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Subgroup analysis-mean BMI

Most of the studies included in the analysis provided data on BMI. A subgroup analysis based on mean BMI (whether ≥ 30 kg/m2) was executed to determine the presence of the effects of BMI on serum cystatin C levels. Results of the analysis revealed elevated serum cystatin C levels among patients with OSAHS compared with controls in both subgroups (i.e., BMI > and < 30 kg/m2). Specifically, those with a mean BMI ≥ 30 kg/m2 exhibited an SMD = 1.33 (95%CI: 0.76–1.91, P < 0.001), whereas those with a mean BMI < 30 exhibited an SMD = 0.61 (95%CI: 0.44–0.78, P < 0.001) (Table 3).

Subgroup analysis-mean age

A subgroup analysis was executed based on mean age (whether ≥ 60 years). In the subgroup with mean age < 60 years, serum cystatin C levels were higher in the OSAHS group in comparison to the control group (SMD = 0.62, 95% CI: 0.45–0.78, P < 0.001). In the subgroup with mean age ≥ 60 years, the levels of serum cystatin C were heightened in the OSAHS group in comparison to the control group (SMD = 1.47, 95% CI: 0.90–2.04, P < 0.001) (Table 3).

Subgroup analysis-ethnicity

Subgroup analysis was carried out to investigate the possible sources of heterogeneity. Subjects were categorized as per ethnicity: Asian (n = 29 studies) and Caucasian (n = 2 studies). In the Asian population, serum cystatin C levels were elevated in the case group in comparison to the control group (SMD = 0.73, 95%CI: 0.54–0.92, P < 0.001). In the Caucasian population, these cystatin C levels exhibited the same pattern (SMD = 0.70, 95%CI: 0.37–1.03, P < 0.001) (Table 3).

Subgroup analysis-study design

Subgroup analyses were executed as per the study design to account for the possible heterogeneity that may arise from different study designs. Among the studies included, 25 were case-control studies, and collective outcomes highlighted that serum cystatin C levels in patients with OSAHS were heightened in comparison to the controls (SMD = 0.69, 95%CI: 0.53–0.85, P < 0.001) (Table 3). Furthermore, 6 studies had a cross-sectional design, and the combined outcomes highlighted that serum cystatin C levels were heightened in patients with OSAHS relative to controls (SMD = 0.86, 95%CI: 0.08–1.64, P = 0.03) (Table 3).

Subgroup analysis-comorbid hypertension

Seventeen studies included patients with OSAHS combined with comorbid hypertension. The meta-analysis implied that serum cystatin C levels were elevated in individuals afflicted with OSAHS combined with comorbid hypertension than in healthy controls (SMD = 0.43, 95% CI: 0.33–0.53, P < 0.001) (Table 3). Fourteen studies included patients with OSAHS alone. The meta-analysis suggested that patients with OSAHS had heightened levels of serum cystatin C than healthy controls (SMD = 0.94, 95% CI: 0.61–1.27, P < 0.001) (Table 3). The outcomes imply that serum cystatin C levels were higher in patients with OSAHS than in healthy controls, regardless of the presence of comorbid hypertension.

Sensitivity analysis

Plots for the “one-study-removed” analyses, which provide valuable insights into the stability of the pooled results regarding serum cystatin C levels in patients with OSAHS in comparison to controls, are presented in Supplementary Fig. 1.

Publication bias

Funnel plots were utilized to examine publication bias in studies investigating the disparities in serum cystatin C levels between patients with OSAHS and controls. The funnel plot presented in Supplementary Fig. 2 exhibited symmetry, indicating the absence of publication bias. This conclusion was further supported by statistical analysis, as evidenced by the outcomes of Egger’s test. The calculated t-value of 1.35 and P-value of 0.188 indicated no statistically significant publication bias.

Circadian variation in cystatin C levels

The meta-analysis exhibited no significant circadian variation in either urinary or serum cystatin C levels (urinary cystatin C: SMD=-0.10, 95% CI: -0.40-0.20, P = 0.520; serum cystatin C: SMD = 0.15, 95% CI: -0.24- 0.54, P = 0.455) (Supplementary Fig. 3). As per the GRADE assessment, there was a moderate certainty of evidence for cystatin C circadian variation.

Association of cystatin C levels with stroke, MACEs, and all-cause mortality

Elevated serum cystatin C concentration functioned as a risk factor for stroke occurrence in elderly patients with OSAHS, independent of other factors such as gender, BMI, and hypertension (quartile 4 adjusted HR = 2.16, 95% CI = 1.09–6.60, P = 0.017) (Fig. 4). In addition, high levels of serum cystatin C were independently linked to a heightened risk of MACEs (quartile 4 adjusted HR = 5.30, 95% CI = 2.28–12.3, P < 0.001) and all-cause mortality (quartile 4 adjusted HR = 9.66, 95% CI = 2.09–44.72, P < 0.001) in elderly patients with OSAHS (Fig. 4).

Fig. 4
figure 4

Association between cystatin C levels and stroke, MACEs, and all-cause mortality risk.

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Association of cystatin C levels with PSG indexes

AHI

Nine studies reported Pearson or Spearman COR between serum/plasma cystatin C levels and AHI scores. The AHI score serves as a crucial indicator of OSAHS severity. Considering the possible link between serum/plasma cystatin C levels and OSAHS severity, the relationship between serum/plasma cystatin C levels and AHI scores in the included population was subjected to pooled analysis using the “meta “R package. According to the outcomes of the analysis, a positive correlation was documented between these two variables (COR = 0.33, 95% CI 0.17–0.47; P < 0.001), as illustrated in Fig. 5A. A moderate certainty of evidence was identified in the GRADE assessment.

Fig. 5
figure 5

Funnel plot of effect sizes measured as correlations between cystatin C levels and the AHI, ODI, Mean SaO2, Minimum SaO2. A: AHI, B: ODI, C: Mean SaO2, D: Minimum SaO2

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ODI

Four studies reported Pearson or Spearman COR between serum/plasma serum cystatin C levels and ODI values. The analysis revealed that the two variables were positively correlated (COR = 0.25, 95% CI 0.10–0.38; P < 0.001), as illustrated in Fig. 5B. A moderate certainty of evidence was identified in the GRADE assessment.

Mean SaO2

Three studies reported Pearson or Spearman COR between serum/plasma serum cystatin C levels and mean SaO2. The analysis indicated that the two variables were negatively correlated (COR=-0.18, 95% CI -0.32–0.02; P = 0.005), as illustrated in Fig. 5C. A moderate certainty of evidence was identified in the GRADE assessment.

Minimum SaO2

Three studies reported Pearson or Spearman COR between serum/plasma serum cystatin C levels and minimum SaO2. The analysis showed a negative correlation between the two variables (COR=-0.20, 95% CI -0.35-0.05; P = 0.001), as shown in Fig. 5D. A moderate certainty of evidence was identified in the GRADE assessment.

Comparison of serum/plasma cystatin C concentrations in patients with OSAHS before and after treatment with surgery or CPAP

Four studies reported alterations in the level of serum/plasma cystatin C in patients with OSAHS prior to and after CPAP treatment. The meta-analysis exhibited a significant decrease in serum/plasma levels in patients with OSAHS following 6 months of CPAP treatment (pre-CPAP vs. post-CPAP, SMD = 0.64, 95% CI: 0.08–1.20, P = 0.024), with a moderate certainty of evidence as per the GRADE assessment (Fig. 6).

Fig. 6
figure 6

Forest plot of SMD and its 95% CI for cystatin C levels in pre-CPAP treatment group compared to post-CPAP treatment group in meta-analysis

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Surgery was performed to treat OSAHS in two studies. Mutlu et al. [34] revealed the absence of any significant difference in plasma cystatin C levels measured preoperatively and 6 months postoperatively in children who underwent adenoidectomy or adenotonsillectomy (784.11 ± 228.72 ng/mL vs. 791.79 ± 137.51). Mutlu et al. [34] noted a non-significant reduction in serum cystatin C levels after tongue and palate flap surgery in patients with OSAHS (458.9 ± 131.6 ng/mL vs. 457.7 ± 114.7). The SMD value was − 0.02 (95% CI=-0.38-0.34, P = 0.923) in the pooling analysis of the two studies, with a moderate certainty of evidence as per the GRADE assessment (Fig. 6).

Discussion

The relationship between serum/plasma cystatin C and OSAHS has garnered widespread attention. However, the differences in serum/plasma cystatin C levels between patients with OSAHS and those without the condition are controversial. The current meta-analysis revealed that serum/plasma cystatin C levels were heightened in patients with OSAHS in comparison to the controls. In addition, as the severity of OSAHS increased, the rise in serum cystatin C became more pronounced. Circadian variations in serum cystatin C levels were not significant in patients with OSAHS. A significant decrease in the level of serum cystatin C was noted in patients with OSAHS treated with CPAP for more than 3 months. Additionally, cystatin C levels may be strongly linked to the risk of MACEs in patients with OSAHS. Cystatin C levels were also positively correlated with the AHI and ODI indexes. Moreover, a negative correlation was noted between cystatin C levels and both minimum SaO2 and mean SaO2. In the sensitivity analysis, removing each study individually did not alter the pooled results. Consequently, these findings underscore the high reliability of this meta-analysis.

Cystatin C, a non-glycosylated protein with a large relative molecular weight consisting of 122 amino acids, is synthesized by all nucleated cells in the human body. Remarkably, its production remains unaffected by factors like gender, muscle mass, type of diet, drugs, and other external influences. Consequently, its concentration in the body remains highly constant [43, 44]. The molecular mass of cystatin C is very small. The positive charge carried by cystatin C allows it to pass freely through the glomerular filtration membrane, and once filtered, it is completely reabsorbed and degraded in the proximal tubule. Importantly, it does not re-enter circulation nor is it secreted by the renal tubule. Hence, the concentration of serum cystatin C, primarily governed by GFR, serves as a highly sensitive endogenous marker for assessing glomerular filtration function [45]. Research indicates that cystatin C serves as an ideal indicator of GFR [46]. Cystatin C reflects changes in GFR rapidly, whereas blood creatinine begins to rise only when GFR falls below 50%. significantly, within the early stages of kidney damage, serum creatinine and blood urea nitrogen are usually in the normal range [47]. When patients with OSAHS present with abnormal urinary protein and routine renal function indices, they have already reached the middle to late stage of renal damage, and some of them may develop end-stage renal disease. The cystatin C exhibits superior sensitivity to that of serum creatinine when renal function is only mildly reduced. Therefore, cystatin C is an ideal marker for GFR determination and is also a powerful endogenous indicator of early renal impairment.

With the in-depth study of OSAHS, changes in renal function caused by OSAHS have gradually been reported globally. The most important pathophysiologic mechanism of renal damage caused by OSAHS is intermittent hypoxia. Intermittent hypoxia can stimulate the sympathetic nervous system, leading to endothelial dysfunction, oxidative stress, and inflammatory response, eventually resulting in renal damage [48]. Hypoxia caused by sleep abnormalities can alter the sympathetically innervated efferent arteriole tone, causing impaired glomerular capillary hemodynamics and thus affecting glomerular filtration [49, 50]. Buehner NJ et al. [51] tested serum creatinine to evaluate the glomerular filtration function in 57 individuals diagnosed with OSAHS with an AHI of 26.7 ± 26.1 beats/h, alongside 24 control subjects. Their findings revealed a significant increase in serum creatinine levels in the OSAHS group in comparison to those in the control group. This is indicative of the influence of OSAHS on glomerular filtration function. The outcomes of the current research demonstrated that serum cystatin C level was significantly higher in patients with OSAHS than in healthy controls in both cross-sectional and case-control studies, suggesting the effect of OSAHS on renal function. The propensity of OSAHS to lead to renal impairment aligns with the conclusions drawn by Buehner NJ et al., supporting the notion of a link between OSAHS and renal impairment [51]. The outcomes of the current research revealed a progressive elevation in serum cystatin C levels with OSAHS severity. This result suggests that renal function is impaired to varying degrees at all stages of OSAHS progression, and a more severe OSAHS condition may lead to a greater renal impairment. Nevertheless, another study reached a different conclusion, asserting that OSAHS does not lead to alterations in renal function [52]. This disparity in findings could potentially be attributed to the insidious nature of OSAHS-caused renal function damage, which may not be readily apparent in certain settings. Therefore, it is challenging to detect positive results on routine tests in the early stages. Therefore, the search for a reliable and early indicator for OSAHS-caused renal impairment is particularly important in active intervention and clinical work, presenting certain social and economic significance. OSAHS is prone to cause renal function damage. Nonetheless, it is difficult to obtain positive results in the early stage of conventional tests. In contrast with traditional renal function indicators, a slight decrease in GFR can cause a significant increase in serum cystatin C levels.

In the current research, elevated serum cystatin C was noted to be more pronounced in elderly patients with OSAHS by subgroup analysis. This outcome is in agreement with prior research. For instance, Fehrman-Ekholm I [53] conducted a study measuring GFR in 50 elderly people over 70 years of age using iohexol plasma clearance, in which cystatin C was significantly elevated with advancing age. Similarly, Werner KB [54] revealed that nondiabetic patients without significant vascular disease exhibited an age-related but heterogeneous decline in renal function. Thus, serum cystatin C tends to be elevated in elderly patients with OSAHS, which may be related to the aging process. Moreover, it is noteworthy that obese patients with OSAHS have higher serum cystatin C concentrations. A previous study demonstrated that obese people generally have significantly elevated serum cystatin C levels [55]. Human adipose tissue, which is found mainly in the subcutaneous and greater omentum, often secretes higher levels of cystatin C [56]. Therefore, obese patients with OSAHS exhibit elevated levels of cystatin C in comparison to their non-obese counterparts. It is important to note that most of our studies originated within Asian populations, with only two studies originating from Caucasian populations. Although the outcome of the pooled effect values implies that serum cystatin C concentrations were heightened in patients with OSAHS in comparison to controls in both populations, the insufficient literature included may lead to geographic limitations in the applicability of the results.

Circadian variation in cystatin C levels is not prominent in patients with OSAHS. Cystatin C levels are closely related to GFR. Previous studies have shown that the circadian variation or circadian rhythm of GFR is a physiological phenomenon. Koopman MG [57] et al. found that GFR varied by an average of 30% over a 24-hour period from a peak at 3:00 p.m. to a nadir at 3:00 a.m. by measuring inulin clearance in 11 healthy subjects. These findings suggest that in healthy individuals, GFR experiences a decline during nighttime hours and rebounds during the daytime, indicating a clear circadian rhythm. However, in patients with chronic kidney disease, the typical nocturnal decrease in GFR may not occur, as diseased kidneys may continue to be hyperfiltered at night. Hilderink [58] et al. reported a less prominent circadian rhythm of cystatin C in individuals with chronic kidney disease, which aligns with the outcomes of the current study. Therefore, it is plausible that the circadian variation in cystatin C levels, indicative of a circadian rhythm, may no longer be prominent following renal damage caused by OSAHS.

In addition, serum cystatin C level in the OSAHS group exhibited significant correlations with AHI and ODI, while displaying negative correlations with minimum and mean SaO2. These findings suggest a potential link between OSAHS-induced renal impairment and nocturnal hypoxia. According to numerous studies in recent years, the possible mechanisms of OSAHS-induced cystatin C elevation are as follows: (1) Hypoxemia activates the renin-angiotensin system, excites sympathetic nerve activity, and stimulates the increased secretion of angiotensin-II and endothelin, which leads to renal vasoconstriction, reduced renal blood flow, and a decrease in GFR [59, 60]; (2) Apnea-induced hypoxia and hypercapnia can lead to increased pulmonary artery pressure, which in turn increases the right ventricular pressure load. Apnea itself increases negative thoracic pressure and venous returned blood volume. Both aspects can result in increased right atrial pressure and elevated glomerular capillary hydrostatic pressure, which can lead to changes in the glomerular basement membrane structure and may affect renal function in patients with OSAH; (3) During the sleep process in patients with OSAHS, intermittent obstruction of the upper airway causes recurrent episodes of apnea and a decrease in oxygen saturation. Then, hyperventilation occurs to restore blood oxygen. This hypoxia/reoxygenation, similar to ischemia/reperfusion [61], produces excessive oxygen free radicals, leading to the development of oxidative stress. This process may cause the fusion of foot processes of glomerular epithelial cells, leading to structural damage of renal tissue [62]. (4) Patients with OSAHS often exhibit concurrent cardiovascular disorders, such as coronary artery disease and hypertension [63, 64], which can contribute to renal function impairment. In this study, serum cystatin C was noted to be increased in patients with OSAHS with comorbid hypertension and those without hypertension. Interestingly, the elevation in serum cystatin C was more pronounced in patients with OSAHS who did not have comorbid hypertension. Mechanistically, patients with comorbid hypertension are usually treated aggressively with antihypertensive medication, which improves GFR and reduces serum cystatin C concentrations.

Serum cystatin C serves as an independent risk factor for cardiovascular disease in patients with OSAHS. Research has revealed a strong association between serum cystatin C and carotid intima-media thickness and left ventricular hypertrophy in hypertensive patients [65]. Consequently, serum cystatin C emerges as a sensitive indicator for detecting target organ damage associated with cardiovascular disease. Serum cystatin C is involved in the development of atherosclerosis and enhances the predictive accuracy of coronary heart disease [66]. Mechanistically, cystatin C may indirectly reflect the disease severity of OSAHS. OSAHS itself can trigger oxidative stress during chronic nocturnal hypoxia, leading to vascular endothelial dysfunction. In addition, cystatin C exhibits high stability. Both cystatin C and its associated degradation products exert a certain effect on the phagocytosis and chemotaxis of neutrophils and participate in the process of inflammatory response in vivo. This involvement accelerates the deterioration of endothelial function and contributes to the progression of atherosclerosis [67,68,69]. Intermittent hypoxia is an important cause of the development of concomitant cardiovascular diseases. Therefore, improving upper airway obstruction and correcting intermittent chronic hypoxia are important strategies for the treatment of OSAHS. After prolonged CPAP treatment, the serum cystatin C levels of the afflicted individuals decreased significantly. Mechanistically, CPAP effectively addresses intermittent hypoxia in patients with OSAHS, thereby reducing oxidative stress, improving endothelial function, and reversing the early damage of renal function, ultimately resulting in decreased cystatin C release. Unfortunately, there is no literature reporting the duration of CPAP treatment for this reduction in serum cystatin C levels. The follow-up time of most studies was 3 months [33], and a longer follow-up period is needed to observe the difference in the efficacy of CPAP treatment for serum cystatin C levels. However, it is noteworthy that serum cystatin C did not diminish significantly in surgically treated patients with OSAHS. One possible explanation for this phenomenon is that a subset of the patients who underwent surgery were children. Children tend to possess greater renal compensatory capacity and cystatin C excretion than adults. Moreover, the limited number of patients undergoing surgery may have introduced bias into the results. Therefore, it is imperative to include a larger cohort of children in future investigations to obtain more comprehensive insights.

Typically, heterogeneity among studies in meta-analyses often stems from various factors, including characteristics of the study population, the quality of the included studies, and differences in study design. In search of an explanation for the observed heterogeneity and its possible sources, subgroup analyses were performed based on several key variables. These included disease severity, mean age, mean BMI, ethnicity, presence of comorbid hypertension, and type of study design. Unfortunately, no significantly lowered I2 values were detected by subgroup analyses, suggesting that none of these factors were a source of heterogeneity. In addition, sensitivity analyses using single-study removal methods failed to identify any specific study responsible for high heterogeneity. We hypothesize that heterogeneity may be influenced by additional factors, like variations in experimental conditions, the method used for cystatin C assay, the timing of blood sample collection, the method of sample storage, as well as individual characteristics such as gender, lifestyle, and smoking status. These factors have the potential to function as confounding variables, exerting influence on cystatin C levels and thereby contributing to the observed heterogeneity across studies.

Strengths and limitations

Liu et al. [70] showed in a previous meta-analysis that cystatin C levels were heightened in patients with OSAHS in comparison to the controls. Their results were consistent with the outcomes of the current research. However, in recent years, increasing literature on the relationship between cystatin C and OSAHS has emerged, in which larger sample sizes are more convincing. Previous studies did not analyze the circadian changes in cystatin C levels or the association between cystatin C levels and OSAHS complications. In our research, we investigate the circadian variation of cystatin C, and did not observe a circadian variation in urinary or serum cystatin C. Additionally, the link of high cystatin C concentrations with the risk of cardiovascular disease in patients with OSAHS was also analyzed in the present meta-analysis, which can help clinicians assess the risk of severe OSAHS-related complications. The increase in cystatin C levels may serve as a risk factor for stroke and MACC in patients with OSAHS. Furthermore, direct evidence establishing a link between cystatin C and OSAHS severity has not yet been acquired in Liu et al.’s study. We quantified the association between cystatin C levels and multiple sleep-monitoring indicators. Serum/plasma cystatin C levels exhibited a positive correlation with AHI scores and ODI. According to the mentioned findings, primary care physicians could initially assess the severity of the disease of a patient based on cystatin C levels and make clinical decisions accordingly. Quantifying the relationship between cystatin C levels and AHI allows outpatient doctors to preliminarily assess the condition of the patients and the severity of hypoxia based on cystatin C levels. There are several innovations in this study compared to previous meta-analyses. Firstly, this represents the most extensive meta-analysis of pertinent literature to date, with subgroup analyses conducted to offer more reliable and robust results. Moreover, the inclusion of recently published research focusing on Chinese populations adds further depth to the meta-analysis. Quite notably, this study found a positive effect of CPAP treatment in reducing cystatin C levels in individuals afflicted with OSAHS. The articles incorporated in this analysis were rated as moderate or high quality, enhancing the feasibility and credibility of the analysis. In patient s with OSAHS, early identification of kidney damage is necessary to protect it from progressive renal damage and complications. Additionally, the absence of significant publication bias indicates that the pooled results could be considered reliable.

Nonetheless, this research is limited in certain respects. First, the study population predominantly consisted of adults afflicted with OSAHS. Therefore, it is imperative to focus attention on assessing the link between cystatin C levels and OSAHS in distinct populations, like children with OSAH. Second, the included studies were mainly case-control and cross-sectional studies. Consequently, we were unable to definitively establish a causal association between OSAHS and cystatin C. Third, renal injury caused by OSAHS is a long-term process. However, the studies incorporated in our meta-analysis were mostly case-control or cross-sectional studies. Therefore, more cohort studies are warranted to validate our findings.

Conclusion

In conclusion, serum/plasma cystatin C levels are significantly heightened in patients with OSAHS. Cystatin C levels are linked to a high risk of cardiovascular disease in patients. Serum/plasma cystatin C levels should be evaluated regularly in patients with OSAHS to mitigate the risk of chronic kidney disease. Cystatin C levels may serve as a clinical indicator to assess OSAHS severity and treatment efficacy. significantly, more prospective cohort studies are essential to diminish the impact of confounding factors on the outcomes of meta-analyses, thereby determining the significant value of cystatin C in the assessment of OSAHS severity.

Data availability

All meta-analysis relevant data are with in the paper.

References

  1. Cortes-Mejia JM, Boquete-Castro A, Arana-Lechuga Y, Terán-Pérez GJ, Casarez-Cruz K, González-Robles RO, et al. Changes in pharyngeal anatomy and apnea/hypopnea index after a mandibular advancement device. Sleep Sci. 2022;15:75–81.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Sun DS, Xu SK, Wang L, Zhang L, Yu HY, Shen JQ. The Weighted Combination of the Epworth Sleepiness Scale and the STOP-Bang Questionnaire Improved the Predictive Value of for OSAHS in Hypertensive patients. Int J Gen Med. 2022;15:6909–15.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Liu C, Kang W, Zhang S, Qiao X, Yang X, Zhou Z, et al. Mandibular Advancement devices prevent the adverse Cardiac effects of Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS). Sci Rep. 2020;10:3394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zheng C, Song H, Wang S, Liu J, Lin T, Du C et al. Serum Uric Acid Is Independently Associated with Risk of Obstructive Sleep Apnea-Hypopnea Syndrome in Chinese Patients with Type 2 Diabetes. Dis Markers. 2019; 2019:4578327.

  5. Keppner A, Maric D, Orlando IMC, Falquet L, Hummler E, Hoogewijs D. Analysis of the hypoxic response in a mouse cortical Collecting Duct-Derived Cell Line suggests that esrra is partially involved in Hif1α-Mediated hypoxia-inducible gene expression in mCCD(cl1) cells. Int J Mol Sci. 2022; 23.

  6. Chen Y, Li Y, Jiang Q, Xu X, Zhang X, Simayi Z, et al. Analysis of early kidney Injury-related factors in patients with hypertension and obstructive sleep apnea Hypopnea Syndrome (OSAHS). Arch Iran Med. 2015;18:827–33.

    PubMed  Google Scholar 

  7. Higgins ML, Haines M, Whalen M, Glaser D, Bylund J. Relationship between changes in buoyant density and formation of new sites of cell wall growth in cultures of Streptococci (Enterococcus hirae ATCC 9790) undergoing a nutritional shift-up. J Bacteriol. 1990;172:4415–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lei L, Li LP, Zeng Z, Mu JX, Yang X, Zhou C, et al. Value of urinary KIM-1 and NGAL combined with serum cys C for predicting acute kidney injury secondary to decompensated cirrhosis. Sci Rep. 2018;8:7962.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Canales MT, Taylor BC, Ishani A, Mehra R, Steffes M, Stone KL, et al. Reduced renal function and sleep-disordered breathing in community-dwelling elderly men. Sleep Med. 2008;9:637–45.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Agrawal V, Vanhecke TE, Rai B, Franklin BA, Sangal RB, McCullough PA. Albuminuria and renal function in obese adults evaluated for obstructive sleep apnea. Nephron Clin Pract. 2009;113:c140–147.

    Article  PubMed  Google Scholar 

  11. Voulgaris A, Archontogeorgis K, Nena E, Tsigalou C, Xanthoudaki M, Kouratzi M, et al. Serum levels of NGAL and cystatin C as markers of early kidney dysfunction in patients with obstructive sleep apnea syndrome. Sleep Breath. 2019;23:161–9.

    Article  PubMed  Google Scholar 

  12. Zhang XB, Lin QC, Deng CS, Chen GP, Cai ZM, Chen H. Elevated serum cystatin C in severe OSA younger men without complications. Sleep Breath. 2013;17:235–41.

    Article  CAS  PubMed  Google Scholar 

  13. Jiang Q, Li TP, Pang B, Wang X, Wang YF. Severe obstructive sleep apnea-hypopnea syndrome with latent renal dysfunction: analysis of 238 cases. J South Med Univ. 2016;36:339–44.

    CAS  Google Scholar 

  14. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hutton B, Catalá-López F, Moher D. [The PRISMA statement extension for systematic reviews incorporating network meta-analysis: PRISMA-NMA]. Med Clin (Barc). 2016;147:262–6.

    Article  PubMed  Google Scholar 

  16. Scartabelli G, Querci G, Marconi L, Ceccarini G, Piaggi P, Fierabracci P, et al. Liver enlargement predicts obstructive sleep apnea-hypopnea syndrome in morbidly obese women. Front Endocrinol (Lausanne). 2018;9:293.

    Article  PubMed  Google Scholar 

  17. Xu X, Zou J, Ding X, Xin D, Ren Y. Clinical value of serum cystatin C by ELISA for estimation of glomerular filtration rate. J Clin Lab Anal. 2004;18:61–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Correction to: Association Between Diethylhexyl Phthalate Exposure and Thyroid Function: A Meta-Analysis by, Kim MJ, Moon S, Oh B-C, Jung D, Choi K, Park YJ. Thyroid. 2019;29:183–192. https://doiorg.publicaciones.saludcastillayleon.es/10.1089/thy.2018.0051. Thyroid. 2019; 29:752.

  19. Yang L, Ren S. Changes of levels of serum monocyte chemoattractant protein-1 and Cystat C in patinets with obstructive sleep apnea-hypopnea syndrome complicated by type 2 diabetes. Int J Respir. 2012;32:506–8.

    Google Scholar 

  20. Xu J, Cheng J, Xu R. The changes of cystatine c in Parkinson’s disease patients with obstructive sleep apnea syndrome. Chin J Neurol. 2014;47:356–69.

    Google Scholar 

  21. Archontogeorgis K, Nena E, Tsigalou C, Voulgaris A, Xanthoudaki M, Froudarakis M et al. Cystatin C Levels in Middle-Aged Patients with Obstructive Sleep Apnea Syndrome. Pulm Med. 2016;2016:8081723.

  22. Hou T, Zhou C, Xie P. Clinical investigation for blood levels of Cystetine C and Superoxide dismutase in patients with obstructive sleep apnea syndrome related hypertension. Chin Circulation J. 2016;31:463–6.

    Google Scholar 

  23. Jiang QQ, Simayi Z, Chen YL, Zhou XH, Zhang XY, Xu XJ, et al. Influencing factors of renal function in hypertensive patients with obstructive sleep apnea-hypopnea syndrome. Volume 45. JOURNAL OF ZHEJIANG UNIVERSITY(MEDICAL SCIENCES; 2016. pp. 261–7.

  24. Wei K, Wen W. Relationship between obesity and the serum cystatin C level in obstructive sleep apnea hypopnea syndrom (OSAHS)patients. Beijing J Stomatology. 2016;24:36–9.

    Google Scholar 

  25. Zhang RF, Ma JG, Liu XX. The test of KIM-1, Cys C and β2-MG to assess the early renal damage in OSAHS patients and its clinical significance. J Clin Otorhinolaryngol Head Neck Surg(China). 2017;31:174–9.

    CAS  Google Scholar 

  26. Geovanini GR, Wang R, Weng J, Jenny NS, Shea S, Allison M, et al. Association between Obstructive Sleep Apnea and Cardiovascular Risk factors: variation by Age, Sex, and race. The multi-ethnic study of atherosclerosis. Ann Am Thorac Soc. 2018;15:970–7.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wang S, Liu C, Liu T. Levels and clinical value of serum homocysteine and cystatin C in patients with obstructive sleep apnea syndrome. CHINA Med HERALD. 2018;15:73–6.

    Google Scholar 

  28. Chen DD, Huang JF, Lin QC, Chen GP, Zhao JM. Relationship between serum adiponectin and bone mineral density in male patients with obstructive sleep apnea syndrome. Sleep Breath. 2017;21:557–64.

    Article  PubMed  Google Scholar 

  29. Song F, Yi HL. Preliminary study on the relationship between OSA and renal function. J Clin Otorhinolaryngol Head Neck Surh(China). 2019;33:298–303.

    CAS  Google Scholar 

  30. Duan Y, Xue M, Zhu N. The changes of serum homocysteine and cystatin C levels and their effects on cognitive function in patients with cerebral infarction accompanied by obstructive sleep apnea hypopnea syndrome. J Clin Med Pract. 2021;25:43–7.

    CAS  Google Scholar 

  31. Edens FW, McCorkle FM, Simmons DG, Yersin AG. Effects of Bordetella avium on lymphoid tissue monoamine concentrations in Turkey poults. Avian Dis. 1987;31:746–51.

    Article  CAS  PubMed  Google Scholar 

  32. Lee S, Noh S, Lee WH. Association of obstructive sleep apnea and diurnal variation of cystatin C. BMC Nephrol. 2024;25:40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhang XB, Jiang XT, Lin QC, Chen X, Zeng HQ. Effect of continuous positive airway pressure on serum cystatin C among obstructive sleep apnea syndrome patients. Int Urol Nephrol. 2014;46:1997–2002.

    Article  CAS  PubMed  Google Scholar 

  34. Mutlu M, Vuralkan E, Akin I, Firat H, Ardic S, Akaydin S, et al. Alteration of serum levels of inflammatory cytokines and polysomnographic indices after uvulopalatal flap surgery in obstructive sleep apnea. Ear Nose Throat J. 2017;96:65–8.

    Article  PubMed  Google Scholar 

  35. Nowicki M, Zawiasa-Bryszewska A, Taczykowska M, Białasiewicz P, Nowak D. The pattern of overnight changes in novel markers of acute kidney injury in patients with obstructive sleep apnea. Adv Clin Exp Med. 2020;29:1065–72.

    Article  PubMed  Google Scholar 

  36. Yoshihisa A, Suzuki S, Owada T, Iwaya S, Yamauchi H, Miyata M, et al. Short-term use of adaptive servo ventilation improves renal function in heart failure patients with sleep-disordered breathing. Heart Vessels. 2013;28:728–34.

    Article  PubMed  Google Scholar 

  37. Mutlu M, Vuralkan E, Yardim Akaydin S, Akin I, Miser E. Effects of adenoid/tonsillectomy on inflammatory response in snoring children with witnessed apnoea. Clin Otolaryngol. 2014;39:266–71.

    Article  CAS  PubMed  Google Scholar 

  38. Su X, Gao Y, Xu W, Li J, Chen K, Gao Y, et al. Association Cystatin C and Risk of Stroke in Elderly patients with obstructive sleep apnea: a prospective cohort study. Front Neurosci. 2021;15:762552.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Li JH, Gao YH, Xue X, Su XF, Wang HH, Lin JL, et al. Association between serum cystatin C levels and long-term cardiovascular outcomes and all-cause mortality in older patients with obstructive sleep apnea. Front Physiol. 2022;13:934413.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Kato K, Takata Y, Usui Y, Shiina K, Asano K, Hashimura Y, et al. Severe obstructive sleep apnea increases cystatin C in clinically latent renal dysfunction. Respir Med. 2011;105:643–9.

    Article  PubMed  Google Scholar 

  41. Chuang LP, Lin SW, Lee LA, Chang CH, Huang HY, Hu HC, et al. Elevated Serum Markers of Acute Kidney Injury in patients with obstructive sleep apnea. J Clin Sleep Med. 2019;15:207–13.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Nowiński A, Czyżak-Gradkowska A, Jonczak L, Korzybski D, Peradzyńska J, Pływaczewski R, et al. Glomerular filtration rate in patients with obstructive sleep apnea: the influence of cystatin-C-based estimations and comorbidity. J Thorac Dis. 2020;12:175–83.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Kwon WS, Kim TS, Nahm CH, Moon Y, Kim JJ. Aberrant cystatin-C expression in blood from patients with breast cancer is a suitable marker for monitoring tumor burden. Oncol Lett. 2018;16:5583–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Singh D, Whooley MA, Ix JH, Ali S, Shlipak MG. Association of cystatin C and estimated GFR with inflammatory biomarkers: the Heart and Soul Study. Nephrol Dial Transpl. 2007;22:1087–92.

    Article  CAS  Google Scholar 

  45. Robles NR, Mena C, Chavez E, Bayo MA, Gonzalez Candia B, Cidoncha A et al. A comparison of cystatin C concentrations between patients with chronic interstitial nephritis and glomerular diseases. J Clin Lab Anal. 2018; 32.

  46. Arceo ES, Dizon GA, Tiongco REG. Serum cystatin C as an early marker of nephropathy among type 2 diabetics: a meta-analysis. Diabetes Metab Syndr. 2019;13:3093–7.

    Article  PubMed  Google Scholar 

  47. Lin Y, Zhang Y. Renoprotective effect of oral rehydration solution III in exertional heatstroke rats. Ren Fail. 2019;41:190–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kanbay M, Ureche C, Copur S, Covic AM, Tanriover C, Esen BH, et al. Kidney transplantation: a possible solution to obstructive sleep apnea in patients with end-stage kidney disease. Sleep Breath. 2023;27:1667–75.

    Article  PubMed  Google Scholar 

  49. Su Y, Li C, Liu W, Liu Y, Li L, Chen Q. Comprehensive analysis of differentially expressed miRNAs in mice with kidney injury induced by chronic intermittent hypoxia. Front Genet. 2022;13:918728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Poonit ND, Zhang YC, Ye CY, Cai HL, Yu CY, Li T, et al. Chronic intermittent hypoxia exposure induces kidney injury in growing rats. Sleep Breath. 2018;22:453–61.

    Article  PubMed  Google Scholar 

  51. Büchner NJ, Henning BF, Hägele KF, Quack IA, Rump LC. [Renal function in hypertensive patients with obstructive sleep apnea]. Dtsch Med Wochenschr. 2004;129:305–9.

    Article  PubMed  Google Scholar 

  52. Mello P, Franger M, Boujaoude Z, Adaimy M, Gelfand E, Kass J, et al. Night and day proteinuria in patients with sleep apnea. Am J Kidney Dis. 2004;44:636–41.

    Article  PubMed  Google Scholar 

  53. Fehrman-Ekholm I, Seeberger A, Björk J, Sterner G. Serum cystatin C: a useful marker of kidney function in very old people. Scand J Clin Lab Invest. 2009;69:606–11.

    Article  CAS  PubMed  Google Scholar 

  54. Werner KB, Elmståhl S, Christensson A, Pihlsgård M. Male sex and vascular risk factors affect cystatin C-derived renal function in older people without diabetes or overt vascular disease. Age Ageing. 2014;43:411–7.

    Article  PubMed  Google Scholar 

  55. Magnusson M, Hedblad B, Engström G, Persson M, Nilsson P, Melander O. High levels of cystatin C predict the metabolic syndrome: the prospective Malmö Diet and Cancer Study. J Intern Med. 2013;274:192–9.

    Article  CAS  PubMed  Google Scholar 

  56. Huo YX, Wei W, Liu Y, Ma YN, Tao JM, Wang NN, et al. Serum cystatin C levels are Associated with obesity in adolescents aged 14–17 years. Front Endocrinol (Lausanne). 2022;13:816201.

    Article  PubMed  Google Scholar 

  57. Koopman MG, Koomen GC, Krediet RT, de Moor EA, Hoek FJ, Arisz L. Circadian rhythm of glomerular filtration rate in normal individuals. Clin Sci (Lond). 1989;77:105–11.

    Article  CAS  PubMed  Google Scholar 

  58. Hilderink JM, van der Linden N, Kimenai DM, Litjens EJR, Klinkenberg LJJ, Aref BM, et al. Biological Variation of Creatinine, Cystatin C, and eGFR over 24 hours. Clin Chem. 2018;64:851–60.

    Article  CAS  PubMed  Google Scholar 

  59. Ghadian A, Einollahi B, Ebrahimi M, Javanbakht M, Asadi M, Kazemi R. Renal function markers in single-kidney patients after percutaneous nephrolithotomy: a pilot study. J Res Med Sci. 2022;27:17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ishikawa SE, Funayama H. Hyponatremia Associated with Congestive Heart failure: involvement of vasopressin and efficacy of vasopressin receptor antagonists. J Clin Med. 2023; 12.

  61. Miller AJ, Sauder CL, Cauffman AE, Blaha CA, Leuenberger UA. Endurance training attenuates the increase in peripheral chemoreflex sensitivity with intermittent hypoxia. Am J Physiol Regul Integr Comp Physiol. 2017;312:R223–8.

    Article  PubMed  Google Scholar 

  62. Radajewska A, Szyller J, Niewiadomska J, Noszczyk-Nowak A, Bil-Lula I. Punica granatum L. Polyphenolic Extract as an Antioxidant to Prevent Kidney Injury in Metabolic Syndrome Rats. Oxid Med Cell Longev. 2023;2023:6144967.

  63. Zeng X, Ma D, Wu K, Yang Q, Zhang S, Luo Y, et al. Development and validation of a clinical model to predict hypertension in consecutive patients with obstructive sleep apnea hypopnea syndrome: a hospital-based study and nomogram analysis. Am J Transl Res. 2022;14:819–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Yang N, Ji Y, Liu Y. Effect of transoral endoscopic adenoidectomy on peripheral blood T-lymphocyte subsets in children with obstructive sleep apnea-hypopnea syndrome and its treatment strategy. Exp Ther Med. 2017;14:3022–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Skalska A, Klimek E, Wizner B, Gasowski J, Grodzicki T. Kidney function and thickness of carotid intima-media complex in patients with treated arterial hypertension. Blood Press. 2007;16:367–74.

    Article  CAS  PubMed  Google Scholar 

  66. Hof D, von Eckardstein A. Risk factors in atherosclerotic coronary heart disease. Ther Umsch. 2009;66:253–9.

    Article  PubMed  Google Scholar 

  67. Benndorf RA. Renal biomarker and Angiostatic Mediator? Cystatin C as a negative Regulator of Vascular endothelial cell homeostasis and angiogenesis. J Am Heart Assoc. 2018;7:e010997.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gao D, Shao J, Jin W, Xia X, Qu Y. Correlations of serum cystatin C and hs-CRP with vascular endothelial cell injury in patients with systemic lupus erythematosus. Panminerva Med. 2018;60:151–5.

    Article  PubMed  Google Scholar 

  69. Ren J, Dong X, Nao J. Serum cystatin C is associated with carotid atherosclerosis in patients with acute ischemic stroke. Neurol Sci. 2020;41:2793–800.

    Article  PubMed  Google Scholar 

  70. Liu T, Zhan Y, Wang Y, Li Q, Mao H. Obstructive sleep apnea syndrome and risk of renal impairment: a systematic review and meta-analysis with trial sequential analysis. Sleep Breath. 2021;25:17–27.

    Article  PubMed  Google Scholar 

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  1. Nianying Fu, Xiaotao Tan and Jie He equally contributed to this work.

Authors and Affiliations

  1. Pulmonology Department, Guanghan Hospital of Traditional Chinese Medicine, DeYang, Sichuan, China

    Nianying Fu

  2. Geriatric Department, Guanghan Hospital of Traditional Chinese Medicine, DeYang, Sichuan, China

    Xiaotao Tan

  3. School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, China

    Jie He

  4. Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China

    Jie He

  5. Clinical Medical College, The First Affiliated Hospital of Chengdu Medical College, Baoguang Street 278, Chengdu, Sichuan, 610500, China

    Jie He

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Fu, N., Tan, X. & He, J. Association between elevated cystatin C levels and obstructive sleep apnea hypopnea syndrome: a systematic review and updated meta-analysis. BMC Pulm Med 25, 56 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12890-025-03508-0

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  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12890-025-03508-0

Keywords

BMC Pulmonary Medicine

ISSN: 1471-2466

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