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ORIGINAL ARTICLE
Year : 2018  |  Volume : 67  |  Issue : 3  |  Page : 231-236

Serum uric acid levels and uric acid/creatinine ratios: affordable biomarkers for predicting chronic obstructive pulmonary disease severity and exacerbations


1 Department of Respiratory Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2 Department of Respiratory Medicine, Faculty of Medicine, October 6 University, Giza, Egypt

Date of Submission26-Mar-2018
Date of Acceptance17-May-2018
Date of Web Publication27-Sep-2018

Correspondence Address:
Hesham A AbdelHalim
Department of Respiratory Medicine, Ain Shams University, 28C, Opera City Compound, Sheikh Zayed, Giza, 12563
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejcdt.ejcdt_39_18

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  Abstract 


Background Chronic obstructive pulmonary disease (COPD) is an essential initiate the conditions of mortality and morbidity.
Objective This study evaluated the clinical importance of measuring the level of serum uric acid (sUA) level and uric acid/creatinine (UA/Cr) ratio in stable COPD patients as objective biomarkers of disease severity and exacerbations
Participants and methods The research involved 283 stable COPD patients and 123 healthy controls. The sUA levels and sUA/Cr ratios in both groups were assessed and compared; their correlations with the clinical, class of severity, number of exacerbations per year, spirometry parameters, oxygen saturation, and C-reactive protein were investigated. Linear regression analysis was done to examine the most predictors for severity and exacerbations, receiver operating characteristic curve for risk of exacerbation, and severity of COPD were reported to study the cut-off values, sensitivity, and specificity of both sUA and UA/Cr ratio.
Results There were significant correlations between both sUA, and UA/Cr ratio with the number of exacerbations and hospitalizations per year, all spirometry data, and C-reactive protein. A linear regression shows significance (F=374, P<0.001) and accounts for 88% of exacerbation frequency. The most powerful predictors were UA/Cr ratio [95% confidence interval (95%CI): 0.003–0.047] followed by UA (95%CI: 0.021–0.195) and then smoking (95%CI: 0.029–0.045). Receiver operating characteristic curves for the evaluation of the performance of both UA levels and calculated UA/Cr ratio in predicting the frequency of exacerbations revealed that UA has a lower predicting power for an exacerbation cut-off value of 4.050 (sensitivity: 0.98, specificity: 0.93), whereas the UA/Cr ratio had a good power of prediction for exacerbation; the cut-off value was 8.49 (sensitivity: 0.99, specificity: 0.57).
Conclusion The measurement of sUA levels and the calculated sUA/Cr ratio estimation have a supplementary role in anticipating the severity of COPD and in predicting future exacerbations.

Keywords: chronic obstructive pulmonary disease, exacerbations, severity, uric acid, uric acid/creatinine ratio


How to cite this article:
AbdelHalim HA, AboElNaga HH. Serum uric acid levels and uric acid/creatinine ratios: affordable biomarkers for predicting chronic obstructive pulmonary disease severity and exacerbations. Egypt J Chest Dis Tuberc 2018;67:231-6

How to cite this URL:
AbdelHalim HA, AboElNaga HH. Serum uric acid levels and uric acid/creatinine ratios: affordable biomarkers for predicting chronic obstructive pulmonary disease severity and exacerbations. Egypt J Chest Dis Tuberc [serial online] 2018 [cited 2021 Jan 22];67:231-6. Available from: http://www.ejcdt.eg.net/text.asp?2018/67/3/231/242385




  Introduction Top


Chronic obstructive pulmonary disease (COPD) is an essential initiate the conditions of mortality and morbidity. COPD provokes oxidative stress and lung inflammation, rising in lung parenchyma destruction, and regression of lung functions [1]. Exacerbation of COPD is the chief influence of the severity due to degradation of the patient’s respirational symptoms [1],[2].

The patients’ full recovery has far-reaching post exacerbations, which have an essential prognostic role in COPD as it reflects progressively increasing risk [3].

Degradation of the pulmonary function during exacerbations diminishes oxygen intake, with consequential cellular hypoxia [4]. Tissue hypoxia results in increased purine and adenosine catabolism into uric acid (UA), which contributes to half of the plasma antioxidative capacity [5]. Thus, as it is a strong reducing substance and antioxidant, higher serum uric acid (sUA) levels could be a biomarker of oxidative stress [6], which increases significantly with the occurrence of inflammation systemically [7].

Raised levels of sUA was seen in other respirational disorders, including obstructive sleep apnea [8], increased pulmonary pressure [9], and increased cardiovascular disorders [6]

However, controversy still exists about the correlation between sUA levels and the extent of COPD severity [5],[10],[11],[12].

To our knowledge, there is a gap of knowledge about the clinical importance and efficiency of measuring the level of sUA, sUA/creatinine (Cr) ratio, in COPD patients during stable states as an objective biomarker of disease progression and activity, or stratification of patients for pending exacerbations [13].

This research aims primarily to determine the difference between sUA levels and sUA/Cr ratios in COPD patients and healthful participants; moreover, it aims to investigate the efficiency of this objective biomarkers in predicting the risk of exacerbation and severity of disease.


  Participants and methods Top


The research involved 406 men; all were enrolled at the outpatient chest departments of Ain Shams University and October 6 University Hospitals. They were divided into two groups: the COPD group which included 283 participants who were diagnosed with COPD and categorized following the 2017 Global Initiative for Obstructive Lung Disease (GOLD) criteria, which depend on clinical symptoms and spirometeric data [1]. And the control group which included 123 normal participants.

The exclusion criteria for both groups were: exacerbations in the past 4 weeks at recruitment; participants having other chronic lung diseases, gouty arthritis, chronic renal failure, malignancies, and participants receiving medications that may affect the serum level of either UA or Cr, for example, allopurinol, ethambutol, pyrazinamide, cyclosporine, probenecid, heparin, fenofibrate, and losartan.

The subsequent data were gathered from all contributing participants: detailed medical data involving age, smoking history, calculated modified-Medical Research Council scale for dyspnea, calculated COPD assessment test, sum of exacerbations, and hospitalizations in the prior year. General and local examinations including anthropometric measures (height, weight, and the calculated BMI), thorough examination of the chest followed by chest radiography, spirometry before and after bronchodilator, oxygen saturation using pulse oximeter, and high-sensitivity ‘C-reactive protein’ (CRP) were done. The sUA and Cr were measured in addition to calculated UA/Cr ratio.

The study was permitted by the review board of the Pulmonary Medicine Department of Ain Shams University. An informed written consent was taken from all participants.

Spirometry

The spirometer tests were done at Ain Shams University Hospital using a Spirometrics ENC FlowMate machine “Spirometrics” and “MIR SRL” (Spring Valley, New York, USA) and at October 6 University Hospital by means of a Spirobank GUSB class II machine (MIR SRL, S/N 806734; Rome, Italy). The tests were done before and 20 min after administration of β2-agonist inhaled (400 μg salbutamol), via a metered dose inhaler. The spirometric data values were assessed and interpreted according to the American Thoracic Society/European Respiratory Society guidelines in all participants [14].

Pulse oximetry

Arterial oxygen saturation was measured for each participant using fingertip Beurer Pulse Oximeter PO 80, EAN 4211125/454.40/1 (Beurer GmbH, Söflinger Str. 218 89077 Ulm. Germany).

Laboratory investigations

A venous blood sample was obtained from every participant for high-sensitivity CRP, creatinine and UA, which were accomplished using the standard methods.

Data analysis

The data were described as mean±SD or frequency (percentage). The variables were matched by means of independent sample t-tests for quantitative variables and χ2-test for categorical variables. Simple correlations between variables were tested using Pearson’s correlation coefficient. A linear regression model was performed to examine the concurrent influences of various variables on COPD severity and frequency of exacerbations. Receiver operating characteristic curves were applied to assess the prognostic benefits of UA levels and UA/Cr ratios for expecting the severity of COPD (GOLD stages of C and D) and frequency of exacerbations (≥2 in the previous year). The Statistical Package for the Social Sciences (SPSS version 17; SPSS Inc., Chicago, Illinois, USA) statistical software was applied for the statistical data analyses. Significance was considered in all tests when the P value is less than 0.05.


  Results Top


The study was conducted on 283 participants with COPD with a mean age of 55.93±10 years and 123 normal participants with a mean age of 56.07±9.05 years as a control group; there were no differences obtained on comparison between both groups concerning age and BMI. There were significant differences among both groups as regards smoking amount, smoking status, spirometry variables, oxygen saturation, CRP level, UA, and UA/Cr. The characteristic data and comparison between-group variables are presented in [Table 1].
Table 1 Description and comparisons of data between chronic obstructive pulmonary disease and control groups

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In the COPD group; there were significant direct correlations between UA level and number of exacerbations per year, frequency of hospitalizations per year, and CRP; and inversely with all spirometry data and oxygen saturation. Also there were significant correlations between UA/Cr ratio and the above-mentioned variables ([Figure 1] and [Figure 2]).
Figure 1 Significant direct correlation between serum uric acid and frequency of exacerbations per year (r=0.421, P<0.001).

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Figure 2 Significant direct correlation between serum uric acid/serum creatinine ratio and number of exacerbations per year (r=0.934, P<0.001).

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A linear regression model was created to examine the concurrent effect of various variables on the frequency of exacerbations. The model was statistically significant (F=374, P<0.001) and explains 88% of exacerbation frequency. The most powerful predictors were UA/Cr ratio [95% confidence interval (95%CI): 0.003–0.047] followed by UA (95%CI: 0.021–0.195), then smoking (95%CI: 0.029–0.045; [Figure 3]).
Figure 3 Linear regression model showing the simultaneous influence of different variables on frequency of exacerbations. The model is statistically significant (F=374, P<0.001) and explains for 88% of exacerbation frequency per year. The most powerful predictors are uric acid/creatinine ratio (95%CI=0.003–0.047) followed by uric acid (95%CI=0.021–0.195) then smoking (95%CI=0.029–0.045). CI, confidence interval.

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Receiver operating characteristic curves for the evaluation of performance of both UA level and sUA/Cr ratio in predicting the frequency of exacerbations showed that UA has a low predicting power for exacerbation number per year; area under the curve (AUC) was 0.414, the cut-off value was 4.050 (sensitivity: 0.98, specificity: 0.93), whereas the UA/Cr ratio had a good power of prediction for exacerbation frequency; AUC=0.561, the cut-off value was 8.49 (sensitivity: 0.99, specificity: 0.57; [Figure 4]).
Figure 4 Receiver operating characteristic curves for evaluation of the performance of both serum uric acid level and uric acid/creatinine ratio in predicting the frequency of exacerbations revealed that uric acid has a low predicting power for exacerbation number per year; area under the curve=0.414, cut-off value is 4.050 (sensitivity: 0.98, specificity: 0.93) whereas uric acid/creatinine ratio has a good power of prediction for exacerbation frequency; area under the curve=0.561, cut-off value is 8.49 (sensitivity: 0.99, specificity: 0.57).

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On the other hand, both UA and UA/Cr ratio had a higher prediction level for the severity of COPD (being in the category C or D); AUC=0.819, the cut-off value was 4.25 (sensitivity: 0.97, specificity: 0.87) for UA; and AUC=0.847, the cut-off value was 7.92 (sensitivity: 0.99, specificity: 0.85) for UA/Cr ratio ([Figure 5]).
Figure 5 Receiver operating characteristic curves for evaluation of the performance of both serum uric acid level and serum uric acid/creatinine ratio in predicting the severity of chronic obstructive pulmonary disease. Both uric acid and uric acid/creatinine ratio had a higher prediction level for the severity of chronic obstructive pulmonary disease (being in the category C or D); area under the curve=0.819, cut-off value was 4.25 (sensitivity: 0.97, specificity: 0.87) for uric acid; and area under the curve=0.847, cut-off value was 7.92 (sensitivity: 0.99, specificity: 0.85) for uric acid/creatinine ratio.

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  Discussion Top


This study was based on the beliefs of GOLD guidelines of the combined evaluation of severity of COPD for improved clinical evaluation and better treatment of patients with COPD [1] and prediction of exacerbations in COPD which appeared to be liberated from COPD severity [3].

The study provided objective biomarkers of clinical importance in COPD patients where it established that the levels of both sUA and calculated sUA/Cr ratios were elevated in COPD patients in comparison to the control group. Therefore, it provided a new supporting study with a larger number of stable COPD participants agreeing with previous other studies [12],[15].

On the other hand, there were varying results of few studies which investigated the relationship between sUA levels and COPD, since sUA may be affected in various systemic diseases [10],[16],[17]. Furthermore, it was proved in a previous study that there is a concealed renal impairment in COPD patients [18]. Therefore, this study also investigated the corrected sUA levels depending on serum creatinine levels.

The results of this study evidenced a significant positive correlation between both sUA level and sUA/Cr ratio together with frequency of exacerbations and hospitalizations per year, while it is inversely correlated with spirometry data forced vital capacity, forced expiratory volume in 1 s, forced expiratory volume in 1 s/forced vital capacity ratio, maximum mid-expiratory flow, and peak expiratory flow. Therefore, fortunately, these affordable measured parameters can be economically performed to deduce patients exposed to the risk for COPD exacerbation and severity of the disease.

On the contrary, other instigators determined that the level of sUA positively correlated with improved lung function [19], while, an additional study testified that decreased levels of sUA were accompanied with COPD rather than current smoking status [20].

Since the role of sUA as a marker of tissue hypoxemia, oxidative stress caused by inflammatory process in patients with severe COPD, in which sUA is the product of adenosine degradation [5]. This was verified in this study by the significant positive correlation between both sUA level and UA/Cr ratio together with CRP. Moreover, there were significant negative correlations between both sUA level and UA/Cr ratio together with oxygen saturation.

During the evaluation of the performance of both UA and UA/Cr ratio in predicting the frequency of exacerbations, this study has shown that sUA has a lower predicting power for exacerbation number per year, than UA/Cr ratio with a sensitivity of 0.98, specificity of 0.93) and sensitivity of 0.99 and specificity of0.57.

On the other hand, both sUA and UA/Cr ratio had a higher prediction level for the severity of COPD (being in the category C or D); (sensitivity: 0.97, specificity: 0.87) for UA; (sensitivity: 0.99, specificity: 0.85) for UA/Cr ratio.

Another study also denoted the more specificity of sUA/Cr ratio than serum uric level only with parallel sensitivities at higher cut-off values and more sensitivity with nearly the same specificities at lower cut-off values of exacerbations and severity of the disease [15].

Additionally, earlier studies have evaluated both the sensitivities and specificities of serum levels of UA or sUA/Cr ratios in COPD exacerbation risk, severity of disease, and mortality, which were significantly greater in patients with higher values of sUA/Cr ratios [12],[21].Tracking these outcomes, this study defined that the most powerful predictors of both COPD exacerbations and severity were UA/Cr ratio followed by UA and then smoking.

It was previously realized that higher sUA level was a predicting variable for COPD severity, together with both short-term and long-term mortality. Besides, the failure to wean from mechanical ventilation in COPD associated with respiratory failure was strongly correlated with an increased level of sUA level on admission. The authors considered these results helpful for selecting the time of tracheal extubating and for improving the success of weaning in COPD patients with respiratory failure [12],[22].

Moreover, another study proved that normalizing sUA was established with adequate treatment outcome and improvement of spirometry values [23].

Limitations of this study included absence of female patients, patients receiving long-term oxygen therapy, and noninvasive mechanical ventilation users that might stand for the small population of the general COPD population.

In conclusion, this study considered that the routine metabolic profile measurement of serum level of UA and calculated UA/Cr ratio are higher in patients having COPD than healthy participants, in addition to their supplementary role in anticipating the severity of COPD and predicting future exacerbations.

Therefore, elevated sUA level UA/Cr ratio may serve as a noninvasive meter for COPD severity and hypoxemia in stable COPD patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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