The serum creatinine to cystatin C ratio predicts the risk of acute exacerbation of chronic obstructive pulmonary disease

Abstract

Background: The aims of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) treatment are to minimize the negative impact of the current exacerbation and to prevent the development of subsequent events. Hence, it is important to identify serological indicators that are readily available at the time of hospital admission to assess the prognosis of patients with AECOPD.

Methods: All patients hospitalized in a Department of Respiratory and Critical Care Medicine of tertiary care hospital between January 2021 and December 2021 for AECOPD were analyzed using univariable correlations and binary logistic regression analysis with two models for associations between demographic, clinical and laboratory features and AECOPD risk.

Results: The Cre/Cys C ratio was significantly associated with age (r = –0.206, P = 0.000), weight (r = 0.331, P = 0.000), BMI (r = 0.133, P = 0.007), and FVC% predicted (r = 0.130, P = 0.009). Multiple regression was run to predict the Cre/Cys C ratio from age, weight, BMI, FEV1/FVC ratio and FVC% predicted FABP-4, with F (5, 405) = 24.571, P=0.000, R2 = 0.233. The results showed that the most significant predictors of the Cre/Cys C ratio were age (P=0.007), weight (P=0.000), BMI (P=0.000), and predicted FEV1 (P=0.000). Multivariate analysis was performed to determine whether the Cre/Cys C ratio was a predictor of AECOPD risk. Model 1 showed that a low Cre/Cys C ratio was associated with an increased hospital LOS (odds ratio (OR): -0.114, 95% confidence interval (CI): -0.061- -0.005) and admission to the ICU (OR: 0.951, 95% CI: 0.907-0.996). After adjustment for potential confounding factors, model 2 showed that a low Cre/Cys C ratio was not independently associated with AECOPD risk.

Conclusion: The present study indicated that the Cre/Cys C ratio is an easy, cheap, repeatable and promising tool that allows us to evaluate the risk of AECOPD using serum markers. A low Cre/Cys C ratio was associated with a prolonged LOS and admission to the ICU in AECOPD patients. However, the associations were not independent.

Background

Chronic obstructive pulmonary disease (COPD) is currently the fourth leading cause of death in the world but is projected to be the 3rd leading cause of death by 2020. Many people suffer from this disease for years and die prematurely from it or its complications[1]. COPD has a chronic and progressive course that is often punctuated by “exacerbations”, which are driven by respiratory infections and multiple functional impairments and comorbidities[2–4]. The aims of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) treatment are to minimize the negative impact of the current exacerbation and to prevent the development of subsequent events[5]. Hence, it is important to identify serological indicators that are readily available at the time of hospital admission to assess the prognosis of patients with AECOPD.

The ratio of creatinine to cystatin C (Cre/Cys C) was first reported as a surrogate marker of muscle mass in 2013[6]. It is noninvasive, fast and less expensive than other examination methods for sarcopenia, such as magnetic resonance imaging (MRI) and computed tomography (CT)[7]. On this basis, Cre/Cys C has been proven to be an accurate and inexpensive predictor of sarcopenia in patients with COPD[7], type 2 diabetes[8], and cancer[9]. Moreover, it is correlated with glucose disposal ability and diabetic complications in patients with type 2 diabetes[8]. Sarcopenia is common in patients with COPD[10], which may affect both respiratory muscles and limb muscles and could, therefore, have critical consequences related to the quality of life and prognosis of COPD patients [10, 11]. However, to date, no study has evaluated the relationship of Cre/Cys C levels upon admission for AECOPD with the outcome of hospitalization. As it is a routine blood test, a detailed analysis of Cre/Cys C levels’ relation to risk seems worthwhile. Therefore, this study aimed to specifically investigate the association between Cre/Cys C levels and risk in patients with AECOPD.

Methods

Pulmonary Function Tests

All the enrolled patients underwent spirometry, and the forced expiratory volume during one second (FEV1) and forced vital capacity (FVC) were measured according to the GOLD consensus guidelines [1]. The FEV1, FEV1/FVC, and the ratio of FEV1 to predicted FEV1 (FEV1%) after inhaling bronchodilators were recorded. According to the category of airflow limitation in COPD (based on FEV1 after the administration of a bronchodilator) in patients with FEV1/FVC < 0.70, stable COPD was divided into four subgroups: mild (GOLD 1), ≥ 80% of predicted FEV1; moderate (GOLD 2), 50–80% of predicted FEV1; severe (GOLD 3), 30–50% of predicted FEV1; very severe (GOLD 4), < 30% of predicted FEV1.

Data Collection And Outcome Assessment

Patient demographics, including age, sex, and BMI, were recorded. We collected initial laboratory findings obtained during hospitalization, including serum creatinine and cystatin C levels.

Serum creatinine and cystatin C levels were measured at the hospital laboratory. Serum creatinine levels were measured using the enzymatic method (Beckman Coulter, Japan), while serum cystatin C levels were measured using the latex agglutination turbidimetric immunoassay (Wan Tai Drd, Beijing, China). The Cre/Cys C ratio was calculated by dividing the serum creatinine value by the serum cystatin C value.

The primary outcomes included respiratory support, complications during hospitalization, hospital length of stay (LOS), admission to the intensive care unit (ICU), and mortality. Respiratory support refers to the use of noninvasive ventilators or invasive ventilators during hospitalization due to the condition. Complications are the combination of acute hypoxemic respiratory failure or acute hypercapnic respiratory failure during hospitalization. LOS was obtained by calculating the patient's admission time and discharge time. Mortality refers to death during hospitalization at this visit.

Results

Study participant characteristics

A total of 411 patients were included in the present study. The mean age of the participants was 70.49 years, and the age range was 38–95 years. There were 246 males (59.85%) and 165 females (40.15%). The mean Cre/Cys C ratio was 75.95 ±14.58. The noninvasive ventilation rate, acute hypercapnic respiratory failure rate, ICU admission rate, and mortality rate were 11.68%, 22.87%, 2.92%, and 0.24%, respectively.

In the low-Cre/Cys C ratio group, there were no significant differences in the different airflow limitation severity groups, including weight (P=0.113), BMI (P=0.445), creatinine level (P=0.419), cystatin C level (P=0.875), and Cre/Cys C ratio (P=0.255). However, the age of the mild group was significantly higher than that of the other group (P=0.015). The male ratio was also higher than that in the other group (P=0.000). (Table 1).

In the high-Cre/Cys C ratio group, compared with the mild, severe, and very severe groups, the moderate group had a significantly elevated BMI (P=0.041). There were no significant differences in other parameters. The specific results are presented in Table 1.

Comparisons of parameters between the low-Cre/Cys C ratio group and the high-Cre/Cys C ratio group showed that the high-Cre/Cys C ratio group had a significantly higher male ratio (76.1 vs. 43.7%, P=0.000), weight (57.11±9.65 vs. 51.93±11.42, P=0.011), BMI (22.66±3.37 vs. 22.27±4.29, P=0.024). There were no significant differences in other parameters. The specific results are presented in Table 1.

Outcomes

In the low-Cre/Cys C ratio group, the noninvasive ventilation ratio (P=0.000) and acute hypercapnic respiratory failure ratio (P=0.000) of the very severe group were significantly higher than those in the other group (P=0.015).

In the high-Cre/Cys C ratio group, compared with the mild, moderate, and severe groups, the very severe group had a significantly elevated noninvasive ventilation ratio (P=0.000) and acute hypercapnic respiratory failure ratio (P=0.000). Moreover, the hospital LOS of the very severe group was significantly higher than that of the other group (P=0.005). There were no significant differences in other parameters. The specific results are presented in Table 2.

Comparisons of parameters between the low-Cre/Cys C ratio group and the high-Cre/Cys C ratio group showed that the low-Cre/Cys C ratio group had a significantly higher acute hypercapnic respiratory failure ratio (27.7 vs. 18%, P=0.02), hospital LOS (10.99±5.09 vs. 10.07±3.11, P=0.023). There were no significant differences in other parameters. The specific results are presented in Table 2.

Analysis of the correlation between the Cre/Cys C ratio and clinical parameters

With regard to study parameters, the Cre/Cys C ratio was significantly associated with age (r = –0.206, P = 0.000; Figure 1a, Table 3), weight (r = 0.331, P = 0.000; Figure 1b, Table 3), BMI (r = 0.133, P = 0.007; Figure 1c, Table 3), and predicted FVC% (r = 0.130, P = 0.009; Figure 1e, Table 3). Finally, a multiple regression was run to predict the Cre/Cys C ratio from age, weight, BMI, FEV1/FVC ratio and FVC% predicted. These variables significantly predicted FABP-4, with F (5, 405) = 24.571, P=0.000, R2 = 0.233. The results showed that the most significant predictors of the Cre/Cys C ratio were age (P=0.007), weight (P=0.000), BMI (P=0.000), and predicted FEV1 (P=0.000) (Table 4).

Multivariate analysis was performed to determine whether the Cre/Cys C ratio was a predictor of AECOPD risk. Model 1 showed that a low Cre/Cys C ratio was associated with an increased hospital LOS (odds ratio (OR): -0.114, 95% confidence interval (CI): -0.061- -0.005) and admission to the ICU (OR: 0.951, 95% CI: 0.907-0.996). After adjustment for potential confounding factors, model 2 showed that a low Cre/Cys C ratio was not independently associated with AECOPD risk (Table 5).

Discussion

The Cre/Cys C has previously been used as a surrogate marker of muscle mass in amyotrophic lateral sclerosis [6], in patients undergoing physical checkups [12], in ICU patients [13], in lung transplant candidates [14], and in type 2 diabetic patients [15]. To the best of our knowledge, based on the available literature, this is the first study to explore the association of the Cre/Cys C ratio, a widely available and rapidly measured biomarker, with risk in patients with AECOPD.

Several previous reports showed that the Cre/Cys C ratio was negatively correlated with age[7, 16–18], sex[17], BMI[7, 17–18] and waist circumference[18]. In addition, there were positive correlations between the Cr/Cys C ratio and FEV1 [16, 19], FVC[19] and FVC% predicted[7]. Our results also showed that the male ratio, weight and BMI levels were significantly elevated with a high Cre/Cys C ratio in patients with acute exacerbation of COPD. There was a negative correlation between the Cre/Cys C ratio and age. We consider that the reason that it has been reported that muscle mass decreases 1–2% annually in patients with COPD over 50 years of age[20], but 5–13% of patients over 65 years of age without chronic diseases such as COPD develop sarcopenia[21]. On the other hand, there was a positive correlation between the Cre/Cys C ratio and weight, BMI, and FVC% predicted. Except for BMI, the findings were similar to those of previous studies. However, a prospective study consecutively recruited patients aged 60 years and older and found that the Cre/Cys C ratio was positively correlated with BMI[22]. Previous reports that the Cre/Cys C ratio is a marker for muscle-adjusted visceral fat mass [18] could explain this finding.

A number of studies have explored the risk factors associated with mortality in patients with AECOPD thus far, and it is known that albumin, respiratory rate, blood gas analysis (PCO2, hemoglobin, lactic acid, etc.), inflammation-related indicators, etc., are important prognostic factors for mortality in these patients[23–28]. Our study used another easy and inexpensive tool to assess the risk of AECOPD.

The serum Cre/Cys C ratio has been reported as a predictive marker for the adverse effects of chemotherapy in lung cancer. The association of the Cre/Cys C ratio with clinical outcomes (e.g., malnutrition, frailty, and hospital length of stay) [22], hospital admission[19], 3-year all-cause mortality[22], cardiovascular disease[8], risk of pneumonia[17], and predictors of severe exacerbations 1 has been reported in recent studies. Our results indicated that the acute hypercapnic respiratory failure ratio and hospital LOS were significantly higher in patients with a low Cre/Cys C ratio than in those with a high Cre/Cys C ratio. The low Cre/Cys C ratio showed a significant association with risk in patients with AECOPD, including increased hospital LOS and admission to the ICU ratio. There was no independent association with AECOPD risk following multivariable adjustments. A low Cre/Cys C ratio in patients with COPD is considered to be associated with a high risk of hospitalization, as systemic inflammation due to acute exacerbations causes muscle weakness and poor health[29].

Our study had some limitations. Previous studies have shown that a higher Cre/Cys C ratio was independently associated with a lower risk of 3-year all-cause mortality after adjusting for potential confounders. The mortality of our study was small, and we were not able to determine the correlation between mortality and the Cre/Cys C ratio. Furthermore, it must be replicated in multicentric studies, using a higher number of patients coming from different areas. Finally, this study did not consider the long-term prognosis of the patients, and the prognosis of the patients after discharge could be followed up with in future studies to more accurately assess the long-term risk of patients with AECOPD.

Conclusion

In conclusion, the present study indicated that the Cre/Cys C ratio is an easy, cheap, repeatable and promising tool that allows us to evaluate the risk of AECOPD using serum markers. Additionally, a low Cre/Cys C ratio may be a valuable predictor of the risk of AECOPD. A low Cre/Cys C ratio was associated with a prolonged LOS and admission to the ICU in AECOPD patients. However, the associations were not independent.

Abbreviations

COPD：Chronic obstructive pulmonary disease；AECOPD：acute exacerbation of chronic obstructive pulmonary disease；Cre/Cys C：ratio of creatinine to cystatin C；MRI：magnetic resonance imaging；CT：computed tomography；GOLD：Global Initiative for Chronic Obstructive Lung Disease；FEV1：forced expiratory volume during one second；FVC：forced vital capacity；FEV1%：ratio of FEV1 to predicted FEV1；LOS：hospital length of stay；ICU：intensive care unit；SDs：means ± standard deviations；BMI：body mass index；NA: unable to analyze due to too few events

Declarations

Acknowledgements

Not Applicable

Author contributions

Ling Lei developed experimental design and wrote the main manuscript text ; Yan Li, Xijun Gou generated experimental data; Liang He reviewed and revised the manuscript draft; All authors reviewed the manuscript.

Funding

No funding was obtained for this study

Availability of data and materials

The datasets used and analysed during the current study available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethical Review Committee of the Xindu District People’s Hospital of Chengdu. Owing to the retrospective nature of the study and the anonymity of the data, no informed consent was required from patients.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Author details

¹ Department of Intensive Care Medicine, Xindu District People's Hospital, Chengdu, Sichuan Province, China ; ²Department of Respiratory and Critical Care Medicine, Xindu District People's Hospital, Chengdu, Sichuan Province, China

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Tables

Tables 1 to 2 are available in the Supplementary Files section

Table 4. Results of the multiple stepwise linear regression analysis of the factors associated with the Cre/Cys C ratio.

Table 5. Results of the multiple linear regression analysis to determine the independent predictors of AECOPD risk.

Model 1: nonadjusted model.

Model 2: adjusted for age, sex, weight, BMI, FEV1/FVC ratio, predicted FEV1, and the presence of chronic diseases (hypertension, diabetes, and coronary heart disease).

NA: unable to analyze due to too few events.