Introduction

Tissue hypoxia results in net degradation of adenosine triphosphate to adenosine diphosphate and adenosine monophosphate. This leads to the release of purine intermediates and the purine catabolic end product, uric acid (UA) [6, 14]. Several studies have shown that serum UA is increased in hypoxic states, including in patients with chronic obstructive pulmonary disease (COPD) [2, 10, 14, 20]. Importantly, serum UA has been proposed as a marker for impaired oxidative metabolism and an independent predictor of impaired prognosis in several processes such as congestive heart failure (CHF) [1], pulmonary thromboembolism [22], primary pulmonary hypertension [16], Eisenmenger syndrome [17], or acute myocardial infarction-related future adverse effects [9].

However, few data exist regarding the significance of serum UA in patients with COPD. We assessed whether the presence of higher values of serum UA and serum UA to creatinine ratio is associated with clinical or functional characteristics in stable patients with COPD.

Methods

Fifty-nine consecutive patients with COPD, diagnosed according to international recommendations [3] (postbronchodilator forced expiratory volume in one second [FEV1] to forced vital capacity [FVC] <0.70) and with oxygen saturation greater than 90%, who were attending the outpatient pulmonary clinic were included. Patients were in clinically stable condition (at least one month without exacerbation) and without other significant comorbid conditions. Patients with renal failure (defined as serum creatinine higher than 1.5 mg/dl), hepatic disease, congestive heart failure, diabetes mellitus, or thyroid dysfunction or who used systemic corticosteroids, diuretics, or cytotoxic drugs were not included in this study. All patients were smokers or ex-smokers. The study was approved by the local ethics committee.

Data for serum biochemical variables were obtained in a routine sample blood test. The following data were also recorded: smoking history (pack-years); body mass index (BMI); dyspnea score during normal activities as measured on the modified Medical Research Council scale [12], which ranges from 0 (no dyspnea) to 4 (dyspnea with minimum activities); number of exacerbations of COPD during the last 12 months (unscheduled visits to physician, visits to the emergency room, and hospitalizations); and number of prescribed medicines to treat the COPD (short-acting beta agonists, long-acting beta agonists, anticholinergics, methylxanthines, inhaled corticosteroids, mucolytics, diuretics, oxygen). Spirometry was performed (Datospir 120 D, Barcelona, Spain), and postbronchodilator results were considered. Spirometric reference values for the Mediterranean population were used [18]. Oxygen saturation was measured with a pulse oximeter sensor (Datospir 120 D, Barcelona, Spain). COPD was classified into four categories [3] as follows: mild, FEV1 ≥ 80% of reference value; moderate, 50% ≤ FEV1 < 80% ref.; severe, 30% ≤ FEV1 < 50% ref.; very severe, FEV1 < 30% ref.

Statistical Analysis

Data are presented as mean ± standard deviation (SD) or percentage when indicated. Normal distribution of variables was assessed by means of the Kolmogorov test. To analyze the possible differences between patients with high and low UA values, two groups were defined according to the median value of the sample (according to the median value of the serum UA level and the median value of the serum UA to creatinine ratio, i.e., below or equal to and above the median value). Differences between groups were compared by the unpaired t test, the Mann-Whitney U test, or the chi-squared test when appropriate. To determine the relationship between clinical and functional parameters with serum UA levels and with serum UA to creatinine ratio, Spearman’s rank correlation was used. A two-tailed p value of less than 0.05 was considered statistically significant.

Results

Patients

There were 55 male patients (93%) and 4 female patients (7%). Age (mean ± SD ) was 67 ± 8 years. Twenty-two patients (37%) had a serum UA value higher than the upper normal limit of our laboratory (7 mg/dl). This group did not differ significantly from the remaining 37 patients in the dyspnea index, number of exacerbations, number of prescribed drugs, oxygen saturation, and spirometric values. Patients were divided into two groups according to the median value of serum UA and the median value of the serum UA to creatinine ratio (correcting the serum UA for the serum creatinine level because UA elimination occurs mainly in urine [13]). Characteristics of both groups (low and high serum UA to creatinine ratio) are detailed in Table 1.

Table 1 Patient characteristics according to the serum uric acid to creatinine ratio below and above median value
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Serum Uric Acid Levels

The median value of serum UA was 6.5 mg/dl. Regarding functional and clinical characteristics, patients with serum UA values below and above this value were significantly different only in FVC (percentage of predicted), which was 73 ± 16% and 63 ± 17%, respectively (p = 0.04). There was no significant correlation between serum UA value and any of the functional and clinical parameters, although, in general, patients with more severe COPD have higher levels of serum UA (Table 2). The serum creatinine level in these groups was (mean ± SD) 0.95 ± 0.14 and 1.04 ± 0.17 (p = 0.002).

Table 2 Serum uric acid and serum uric acid to creatinine ratio according to COPD severity
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Serum Uric Acid to Creatinine Ratio

The median value of serum UA to creatinine ratio was 6.7. Patients in whom this ratio was above this median value in general had a higher level of dyspnea and lower spirometric values (Table 1). Although this group of patients had more exacerbations in the previous year, the difference did not achieve statistical significance (p = 0.1). Table 2 shows the serum UA to creatinine ratio according to the COPD severity. The serum UA to creatinine ratio negatively correlated with FVC and FEV1 and positively correlated with dyspnea severity (Table 3).

Table 3 Correlation between serum uric acid to creatinine ratio and clinical characteristics
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Discussion

In the first step of our study, we analyzed the characteristics of the patients according to the serum UA level. The groups of patients with serum UA values below and above the median value did not differ significantly in clinical or functional data. However, these patients did differ in the creatinine level. Because UA elimination occurs mainly in urine [13], in the second step we analyzed the data by correcting the serum UA for the serum creatinine level. Interestingly, in this study we found that patients with a serum UA to creatinine ratio above the median value had lower spirometric values and a higher level of dyspnea. These patients tended to have more exacerbations and lower oxygen saturation, but differences in these parameters did not achieve statistical significance.

Our findings are otherwise not unexpected. An increase in UA is produced as a consequence of purine catabolism secondary to tissue hypoxia [6, 14]. It is to be expected that patients with worse pulmonary function and more dyspnea represent the group of COPD patients with more risk of hypoxia and impaired oxidative metabolism. Unfortunately, in this first clinical approach we have no data about our patients on ventilatory limitation and oxygen desaturation during exercise.

Serum UA has been studied in several conditions associated with hypoxic states, and results consistently show that this parameter reflects a worse situation or a worse prognosis. Epidemiologic studies have shown that uric acid may be a risk factor for cardiovascular diseases and a negative prognostic marker for mortality in subjects with pre-existing heart failure [1]. In patients with pulmonary thromboembolism, serum UA increases in proportion to the severity of the embolism [22]. In patients with pulmonary hypertension, serum UA has an independent association with long-term mortality [16]. Serum UA increases in proportion to hemodynamic severity in adult patients with Eisenmenger syndrome and is independently associated with long-term mortality [17]. Also, serum UA level is a suitable marker for predicting acute myocardial infarction-related future adverse effects [9].

In patients with chronic respiratory disease the value of serum UA has not been clearly evaluated. It is known that the total antioxidant capacity and UA levels are markedly higher in COPD patients compared with healthy controls [7]. In a study (presented as an abstract) of 110 patients with COPD, a significant correlation was found between hypoxemia and UA levels (in stable and exacerbated patients) and between COPD severity and UA level (in stable COPD patients) [11]. However, to our knowledge this study has not yet been published. Several authors have explored the possibility of using the nocturnal increase in the urinary UA to creatinine ratio for detection of sleep hypoxemia in both obstructive sleep apnea and COPD [2, 8, 15, 20]. In a study in Japan of patients with COPD receiving home oxygen therapy, the mortality was significantly higher in those with a higher increase in the serum uric acid to creatinine ratio [21]. As in other studies [16, 20, 22], we found no correlation between serum UA (or serum UA to creatinine ratio) and arterial oxygen saturation. Tissue hypoxia is determined by the balance between arterial oxygen transport and oxygen demands in tissue, and the absence of correlation between arterial oxygen saturation and markers of tissue hypoxia is not surprising. Oxygen transport is determined not only by oxygen saturation but also by the concentration of hemoglobin, the hemoglobin dissociation curve, cardiac output, the distribution of tissue blood flow, and other factors [4].

A positive and significant association between serum UA and several inflammatory markers, including C-reactive protein and interleukin-6, has been described [19]. Very recently, C-reactive protein has been reported to be independently associated with arterial oxygen tension and 6-min walk distance, factors known to predict outcome in COPD patients [5]. In view of these data and our results, we consider that serum UA warrants evaluation as an additional parameter for predicting outcome in COPD.