The association between cystatin C and COPD: a meta-analysis and systematic review

Chronic obstructive pulmonary disease (COPD) is a disease characterized by incomplete reversibility of airflow obstruction, chronic inflammation of the airways, and systemic effects or comorbidities [1‐3]. Although COPD is a preventable and treatable disease, it still brings heavy economic burden to family and the society [4‐6]. However, the pathogenesis of COPD is not completely elucidated, and it is the long-term interaction of many factors including environmental factors and genetic factors [7]. Nowadays, GOLD guidelines recommend using spirometry assessment as a diagnostic and prognostic indicator for COPD [8]. However, fewer than half of the patients have the data from spirometry lung function tests [9, 10]. Therefore, it is of great significance to explore simple and novel biomarkers of COPD for the early diagnosis and monitoring of prognosis.

Cystatin C (Cys C), an inhibitor of cysteine proteinase, belongs to the member of family II of the cystatin super-family [11]. Cys C is an alkaline secreted protein, with a molecular mass of 13.3 kDa, which widely exists in various tissues of nucleated cells and body fluids, and produced by the body’s all nucleated cells [12, 13]. Cys C can protect human cells from improper hydrolysis of proteases inside and outside the body. Previous researches suggest that serum Cys C is entirely determined by the glomerular filtration rate (GFR), and may more accurately estimate GFR than creatinine [14‐16]. It has been suggested that Cys C is valuable in predicting cardiovascular mortality in cardiovascular disease [17, 18]. In recent years, there are many studies on the clinical significance of serum Cys C levels changes in respiratory diseases. It has been studied that Cys C plays a role in pathogenesis of obstructive sleep apnea syndrome [10‐20], lung malignancy [21], pleural effusions [22], and emphysema [23].

Recent studies indicate a possible link between Cys C and COPD [24‐28]; however, the conclusion is not clear. Most studies have shown that serum Cys C levels are higher in the exacerbation group than stable COPD or healthy control [29, 30], but Selder et al. [31] find that serum Cys C levels are lower in exacerbation group than stable COPD. We performed this meta-analysis to clarify the associations between serum Cys C levels and COPD as well as COPD exacerbation. This study might provide new perspectives in explaining the relationship between Cys C and COPD, COPD exacerbation.

This meta-analysis was designed to perform the potential relationship between serum Cys C levels and patients with COPD. The main results of the meta-analysis were as follows:1) the serum levels of Cys C in COPD patients were higher than that in the control; 2) serum Cys C levels in AECOPD patients and SCOPD patients were higher than those in the control group, and the serum Cys C levels in AECOPD patients were higher than that in stable COPD; 3) the serum Cys C levels were independent of ethnic, assay method and study design; 4) serum Cys C levels had a reverse correlation with FEV1%pre or FEV1/FVC.

Chronic obstructive pulmonary disease (COPD) is the most common Chronic respiratory disease, and the airflow limitations are associated with long-term chronic inflammatory responses of lung tissues to harmful gases and particles [7]. FEV1% and the frequency of exacerbations are common indicators for diagnosis and monitoring of treatment response [8]. However, due to the complicated examination of lung function, part of the patients cannot accept lung function as an index to evaluate the therapeutic effect. Therefore, it is necessary to look for sensitive and reliable markers related to COPD in simple sampling methods, which help clinicians diagnose COPD faster and evaluate its treatment effect more accurately.

The imbalance between protease and antiprotease is one of the important pathogenesis of COPD. Under the action of harmful factors, the protease system is stimulated and activated, which causes the synthesis and secretion of protease to be excessive, and the antiprotease system is destroyed and inactivated, which results that the synthesis or secretion of anti-protease is reduced. These together lead to an increase in the breakdown of matrix proteins in lung tissue, which promotes the development and progression of COPD [2].

Cathepsin is a family of cysteine proteases, and cathepsin B, H, L, and S are involved in the pathogenesis of COPD [38]. Cys C is a cysteine protease inhibitor, which is the most extensive and effective inhibitor of cathepsin involved in lung tissue destruction [48]. On the one hand, hypoxemia can damage inflammatory cells in the body and releases a large amount of Cys C, which leads to elevated levels of serum Cys C in patients with COPD [49]. On the other hand, hypoxia causes inflammatory cells such as macrophages to release the cytokines with protease activity, which results in the destruction of elastin and leads to emphysema. However, the increasing and activating of protease stimulates the body to synthesize more anti-protease, which will fight against the decomposition and destruction of protease to tissues. Therefore, the levels of Cys C can predict cathepsin activity indirectly and reliably [26]. Finally, when the body is in a state of hypoxia, the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system will be activated, which leads to the contraction of systemic small blood vessels, the decreasing of glomerular blood flow into the aorta, the reducing of effective glomerular filtration rate, and ultimately increasing serum Cys C levels.

This meta-analysis indicated that serum Cys C levels were higher in COPD. Nakajima et al. [26] reported that serum levels of Cys C were significantly higher in COPD patients than control. Previous studies showed that inflammatory parameters such as interleukin-6, resistin, tumor necrosis factor, and CRP were significantly correlated with Cys C, suggesting that the elevation of Cys C was secondary to the inflammatory processes in the lung [31, 38, 50]. These all above cytokines have been found to be closely related to COPD, which indicated that elevated Cys C levels might be associated with pulmonary inflammation.

Consistent with previous studies, we found that the elevated levels of Cys C were significantly correlated with disease status and lung function. Hu et al. [24] found that the elevated Cys C levels was an important and independent risk factor of increased mortality in a hospital setting during COPD exacerbation, Formiga et al. [51] indicated that inspiratory muscle function was reduced with greater degrees of inflammation in COPD as expressed higher levels of Cys C. Combining with the results of previous studies and this meta-analysis, we thought that the elevated levels of serum Cys C might indicate the exacerbation and progression of COPD.

In this meta-analysis, we noted that there was great heterogeneity in the included studies. Moreover, we performed Egger’s test, which revealed that there was significant evidence of publication bias in the included studies. Although we used the random-effect model when we found heterogeneity, this increases the probability of type I error. We carried out a sensitivity analysis to assess the stability of this meta-analysis. Sequential removal of each study did not alter the conclusions, suggesting that these results were reliable. We also performed meta-regression analysis and subgroup analysis to perform the possible sources of heterogeneity and reduce the occurrence of type I errors.

Before explaining our results, several limitations of this meta-analysis should be pointed out. First, although some confounding factors might influence the results of the meta-analysis, we did not conduct a subgroup analysis of smoking status due to insufficient original data, the lack of original data also might limit sufficient statistical power to evaluate the potential effects of Cys C levels on the development of COPD. Second, although we tried to gather the original data from the study authors, few authors responded to the data request. Hence, we adopted accepted methods to extract and synthesize data. Third, the concentration of serum Cys C is affected by a variety of diseases, and a part of these diseases are associated with COPD. Previous studies have indicated that Cys C is strongly associated with renal function [52, 53], chronic hypoxia could also lead to renal dysfunction in patients with COPD [54]. Although patients with kidney disease were excluded when we included the literature, the renal dysfunction caused by COPD might affect the concentration of serum Cys C, which may have some influence on the results. Fourth, the sample sizes in most cited studies were small, and methodologic design may be flawed in smaller studies, the conclusions of smaller studies might be impacted by confounding factors, which might have an impact on our results. Fifth, the probability of death due to COPD is much higher in Asian, particularly China, than western countries [55, 56], and Caucasians with COPD have lower serum Cys C level compared with Asians COPD patients [28, 30, 38, 42]. Although we had done a review of the available published studies, most studies included were from Asia, therefore the promotion of conclusions had some limitations. Sixth, many studies have indicated that elevated Cys C levels may be associated with pulmonary inflammation. However, due to the insufficient data, we did not perform the causal mediation analysis to explore whether serum Cys C was an inflammatory mediator in the development of COPD [57], which made the extension of the results limited. Finally, only published studies were retrieved in this meta-analysis and possible publication bias might exist, and Egger’s test found significant evidence of publication bias. Therefore, more keywords should be used to retrieve more studies for further evaluating the relationship between Cys C levels and COPD.

Conclusively, the current meta-analysis suggests that, serum Cys C levels are higher in patients with COPD (both stable COPD and AECOPD) compared to controls. Serum Cys C levels are reversely correlated with FEV1%pre or FEV1/FVC. The results provided an improved understanding of the roles of Cys C in COPD development and progression. Further large-scale, unified and well-designed studies are needed to explore the relationship between Cys C and COPD, COPD exacerbation.