Microalbuminuria and Hypoxemia in Patients with Chronic Obstructive Pulmonary Disease Ciro Casanova1,2, Juan P. de Torres3, Juan Navarro2,4, Armando Aguirre-Jaı´me2, Pablo Toledo2, Elizabeth Cordoba2, Rebeca Baz2, and Bartolome´ R Celli5 1 Pulmonary Department, 2Research Unit, and 4Nephrology Department, Hospital La Candelaria, Tenerife, Spain; and 3Pulmonary Department, Clı´nica Universitaria de Navarra, Pamplona, Spain; 5Pulmonary Division, Brigham and Women’s Hospital, Boston, Massachusetts
Rationale: Microalbuminuria (MAB), a marker of endovascular dysfunction, is a predictor of cardiovascular events and all-cause mortality in the general population. There is evidence of vascular dysfunction in patients with chronic obstructive pulmonary disease (COPD). Objectives: To assess the prevalence and relationship of MAB with clinical and physiological parameters in stable patients with COPD. Methods: We measured urinary albumin rate (urinary albumin to creatinine ratio: UACR), smoking history, arterial blood pressure, gas exchange, body mass index, lung function, BODE index (body mass index, airflow obstruction, dyspnea, exercise performance), and comorbidity index in 129 patients with stable COPD and 51 smokers with normal spirometry without known cardiovascular disease. MAB levels were compared between groups. A multivariate analysis was performed to determine the best determinants of MAB levels. Measurements and Main Results: MAB was higher in patients with COPD than in control smokers (8 [5th295th percentile (P5–95), 2.9– 113] vs. 4.2 [P5–95, 1.8–22.7] mg/g, P , 0.001]). The difference remained significant even after using the standard pathologic threshold (MAB, 30–299 mg/g in women and 20–299 mg/g in men; 24% in patients with COPD vs. 6% in control smokers; P 5 0.005). In patients with COPD, there was a negative correlation between PaO2 and MAB (r 5 20.40, P , 0.001). Using multivariate analysis, MAB was only associated with the PaO2 (relative risk, 0.934; 95% confidence interval, 0.880–0.992; P , 0.001) and with the systolic arterial blood pressure (relative risk, 1.034; 95% confidence interval, 1.011–1.057; P 5 0.003). Conclusions: MAB is frequent in patients with COPD and is associated with hypoxemia independent of other cardiovascular risk factors. Further studies are necessary to investigate whether MAB could be an early simple biomarker of cardiovascular compromise in patients with COPD. Keywords: chronic obstructive pulmonary disease; microalbuminuria; hypoxemia; biomarker; cardiovascular risk
Chronic obstructive pulmonary disease (COPD) will become the third leading cause of death by 2020. COPD is associated with an abnormal inflammatory response in the lungs, with important extrapulmonary manifestations and with the presence of multiple comorbidities. Several cytokines and inflammatory mediators have been implicated, but the link between COPD and its systemic expressions are not well understood (1, 2). Cardiovascular disease is a major cause of mortality in COPD, particularly in patients with mild to moderate severity (3–5). The likelihood of identifying cardiovascular subclinical abnormalities in patients with COPD during daily clinical practice strongly (Received in original form March 5, 2010; accepted in final form June 17, 2010) Correspondence and requests for reprints should be addressed to Ciro Casanova, M.D., Associate Professor, Universidad de La Laguna, Tenerife, Respiratory Research Unit, Pulmonary Department, Hospital Universitario La Candelaria, Carretera del Rosario n8 145, 38010 Santa Cruz de Tenerife, Spain. E-mail: casanovaciro@gmail.com Am J Respir Crit Care Med Vol 182. pp 1004–1010, 2010 Originally Published in Press as DOI: 10.1164/rccm.201003-0360OC on June 17, 2010 Internet address: www.atsjournals.org
AT A GLANCE COMMENTARY Scientific Knowledge on the Subject
Cardiovascular disease is a major cause of mortality in patients with chronic obstructive pulmonary disease (COPD). Microalbuminuria (MAB), a marker of endovascular dysfunction, is a predictor of cardiovascular events and all-cause mortality in the general population. What This Study Adds to the Field
MAB is frequent in patients with COPD and is associated with hypoxemia independent of other cardiovascular risk factors. The determination of MAB is simple, inexpensive, and noninvasive, and could be a promising biomarker to identify patients with COPD at increased cardiovascular risk.
depends on the diagnostic techniques used. The widespread use of sensitive diagnostic tests, such as ultrasound scan and a new generation of computed tomography (CT) scans, are good options (6, 7). Recent studies have shown an association between lower FEV1 and emphysema severity with arterial stiffness (8, 9) and endothelial dysfunction (10). Also, vascular alterations, measured from the cross-sectional area of small pulmonary vessels by CT scan, correlate with the magnitude of pulmonary hypertension (11). However, because of the high prevalence of COPD, these tools may not always be practical in the general population for both logistic and economical reasons. The discovery of novel biomarkers to help identify cardiovascular risk in patients with COPD could help individualize therapy for that particular phenotype. Ideally, the biomarker should be inexpensive, noninvasive, and easily assessable (2). C-reactive protein (CRP) has been proposed as one such biomarker and increased serum levels of CRP have been related to increased cardiovascular mortality in mild to moderate COPD (12). However, this finding was described only in epidemiological cohorts and was not replicated in patients with more severe disease (13). In addition, CRP appears not to provide additional prognostic information beyond traditional risk factors in the general population (14). Microalbuminuria (MAB) is a sensitive marker of cardiovascular risk (15, 16). The presence of MAB is consistently associated with arterial stiffness assessed by pulse wave velocity and worse cardiovascular outcomes in patients with diabetes and hypertension, but most importantly in the general population (17–19). MAB has a stronger association with cardiovascular events and death than CRP (14, 20–22). MAB is believed to reflect a state of generalized endothelial dysfunction, and therefore it is an emerging therapeutic target for primary prevention strategies (23).
Casanova, de Torres, Navarro, et al.: Microalbuminuria and COPD
A limited number of studies have evaluated the presence of MAB in patients with COPD, mostly during exacerbations (24– 26). In those studies, the influence of other cardiovascular risk factors was not considered. We hypothesized that MAB is elevated in patients with COPD independently of other cardiovascular risk factors. To test this hypothesis, we determined the prevalence of MAB in a group of patients with COPD and evaluated the relationship of MAB levels with clinical and physiological descriptors of COPD severity and cardiovascular risk factors. A group of smoking subjects without COPD served as control subjects. Some of the results of this study have been previously reported in the form of an abstract (27).
METHODS Study Population A total of 162 outpatients with COPD and a wide range of airflow obstruction from hospitals in Tenerife (n 5 105) and Pamplona (n 5 57) in Spain participated in the study (Figure 1) and signed the consent approved by the Human Review Board. They were consecutively enrolled from May 2006 to January 2010 as part of the BODE (body mass index, airflow obstruction, dyspnea, and exercise performance) cohort (28). COPD was defined by a history of smoking greater than 10 pack-years and a post-bronchodilator FEV1/FVC less than 0.7. Patients were stable for 6 weeks and received optimal therapy according to guidelines. We also studied 60 smokers of more than 10 pack-years without airflow obstruction (FEV1/FVC . 0.7). Exclusion criteria were: history of renal disease or presence of macroalbuminuria (urinary albumin to creatinine ratio > 300 mg/g), cardiovascular disease, uncontrolled comorbidities, such as malignancy, asthma, or other confounding diseases. We recorded history of diabetes, hypertension, and dyslipidemia. Blood pressure was measured following standard recommendations (29).
Clinical Variables Arterial blood gases were measured by arterial puncture, in the morning, sitting at rest (15 min), breathing room air for at least 45 minutes. The alveolar-arterial PO2 difference (A-aPO2) was calculated using the standard formula, assuming a respiratory exchange ratio (R) of 0.8. Lung volumes and spirometry were measured according to American Thoracic Society/European Respiratory Society guidelines (30). The severity of COPD was classified according to American Thoracic Society/European Respiratory Society/Global Initiative for Obstructive Lung Disease (GOLD) (1, 2). The 6-minute walk distance was measured as the better of two walks separated by at least 30 minutes (31). Dyspnea was evaluated by the modified Medical Research Council scale (32). Body mass index was calculated in kg/m2. The FEV1%, body mass index, 6-minute walk
Figure 1. Consort diagram of the study population. COPD 5 chronic obstructive pulmonary disease; CVD 5 cardiovascular disease.
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distance, and modified Medical Research Council values were integrated into the BODE index (28).
Laboratory Methods Morning fasting blood and spot-urine samples were collected simultaneously while at rest, before any other test. Urinary albumin excretion was determined as the urinary albumin (mg) to creatinine (g) ratio (UACR) in the morning urine. Urine albumin concentration was determined by a standard turbidimetric method (coefficient of variation, 5.5%). Serum and urine creatinine concentrations were analyzed using the Jaffe reaction and quantified by a photometric method. Glomerular filtration rate (GFR) was estimated using the validated Modification of Diet in Renal Disease equation (33): 170 [serum creatinine]20.999 [age]20.176 [blood urea]2170 [serum albumin]0.318 (0.762 for women) (1.180 for African American subjects). Renal dysfunction was diagnosed if GFR was less than 60 ml/min/1.73 m2. MAB was defined when the UACR was between 20 mg/g in men and 30 mg/g in women and the upper threshold of 299 mg/g for both sexes (34). Serum levels of glucose, hemoglobin AIc, cholesterol, and albumin were also determined.
Statistical Analysis Data are summarized as relative frequencies for categorical variables, mean (SD) for normally distributed variables, and median (5th295th percentile) for nonnormal data. Comparisons between groups were performed using Student t test, Pearson chi-square, or Mann-Whitney U according to the variable type and distribution. Associations were estimated using Spearman or Pearson linear coefficients. Logistic regression analysis was performed to estimate the relative risk of abnormal UACR adjusting by other confounding factors. The MAB changes over time were evaluated in a subgroup of 52 patients at 12 months. We used the Bland-Altman plot and mixed linear models to express the changes within subjects. Significance level was established as a two-tailed P value of 0.05 or less. Calculations were made with SPSS 15.0 (Chicago, IL).
RESULTS The characteristics of the patients with COPD (n 5 129) and control subjects (n 5 51) are shown in Table 1. Six patients in the COPD group were excluded because their excretion of urinary albumin was 300 mg/g or greater. Three of these patients had diabetes and five had hypertension as well as moderate to very severe COPD (FEV1, 46% [27–72%]; PaO2, 62 mm Hg [56–75]). Patients with COPD were older and had a longer pack-year cigarette exposure than control subjects. No differences were found in history of diabetes mellitus and hypertension between groups. The patients with COPD had significantly higher levels of MAB than smokers without obstruction (median 8 [P5–95, 2.9– 113] vs. 4.2 [P5–95, 1.8–22.7] mg/g; P , 0.001)] and this difference between groups persisted after the analysis was stratified using accepted pathological thresholds (24 vs. 6%; P 5 0.005) (Table 1). The difference between groups remained significant even when patients with diabetes mellitus were excluded (to avoid the possible influence of subclinical diabetes on MAB). In this latter group, the absolute values in patients with COPD compared with control subjects were 8.1 (2.9–114) versus 4.1 (1.7–24.4; P , 0.001), and 23 versus 4.5% (P 5 0.008) as the percentage of patients reaching the pathological threshold (Figure 2). For the whole group, the pack-years of smoking history was not associated with the MAB levels. On the other hand, age showed a weak but significant positive association with the levels of MAB (r 5 0.22; P 5 0.003). To evaluate the impact of age on MAB we performed an analysis of patients between 45 and 65 years of age. There were 59 patients in the COPD group and 33 in the control group. The median age was similar between groups (58 vs. 57 yr; P 5 0.455). Compared with control subjects, the levels of MAB remained higher in patients with COPD
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TABLE 1. BASELINE CHARACTERISTIC OF THE PATIENTS AND CONTROL SUBJECTS INCLUDED IN THE STUDY Patients with COPD (n 5 129) Sex, M/F, n 92/37 Age, yr 65 (10) Pack-years 58 (25) 28 (5) BMI, kg/m2 1.57 (0.69) FEV1, L FEV1, % 61 (21) FVC, % 90 (22) Diabetes mellitus, n (%) 28 (22) Hemoglobin AIc 6 (1.1) Hypertension, n, (%) 42 (33) ACE inhibitors or ARB use, n (%) 32 (26) Systolic arterial pressure, mm Hg 130 (15) Diastolic arterial pressure, mm Hg 76 (11) Statins use, n (%) 44 (34) LDL cholesterol, mg/dl 126 (34) UACR, mg/g* 8 (2.9–113) MAB (UACR > 20 mg/g men 31(24) or > 30 mg/g women), n (%)
Smoking Patients without COPD (n 5 51) P Value 52 34 28 3.25 103 109 6 5.7 15 12 129 80 14 132 4 3
39/12 (10) (15) (5) (0.82) (13) (14) (12) (0.6) (30) (25) (14) (10) (28) (34) (1.8–22.7) (6)
0.484 ,0.001 ,0.001 0.714 ,0.001 ,0.001 ,0.001 0.137 0.173 0.742 0.814 0.567 0.080 0.415 0.293 ,0.001 0.005
Definition of abbreviations: ACE 5 angiotensin-converting enzyme; ARB 5 angiotensin II receptor blocker; BMI 5 body mass index; COPD 5 chronic obstructive pulmonary disease; LDL 5 low-density lipoprotein; MAB 5 microalbuminuria; UACR 5 urinary albumin to creatinine ratio. Data presented as mean (SD) unless otherwise noted. * Median (5th–95th percentile).
whether expressed in absolute values (7.6 [2–86.7] vs. 4.4 [1.9– 18.9]; P 5 0.001) or as the percentage of patients reaching the pathological threshold (23.7 vs. 3%; P 5 0.004). GFR values were normal (>60 ml/min/1.73 m2) in the vast majority of the study participants (96% in patients with COPD and 94% in smokers without COPD). In patients with COPD, the GFR had no relation to the degree of MAB. Patients with COPD and MAB (UACR >20 mg/g for men and >30 mg/g for women) were more hypoxemic and hypercapnic and had higher levels of arterial blood pressure than those without MAB. Indeed, the A-aPO2 was higher in patients with COPD and MAB (Table 2). The A-aPO2 was significantly related to the MAB (r 5 0.24; P 5 0.01). There were no differences in any other parameter (Tables 2 and 3). Multivariable analysis with MAB as the dependent variable showed that PaO2 (relative risk, 0.910; 95% CI, 0.857–0.958; P , 0.001) and systolic arterial pressure (relative risk, 1.034; 95% CI, 1.011–1.057; P 5 0.003) were the only independent and significant predictors of MAB levels (Table 4). PaO2 was the most important predictive factor and showed a negative association with MAB (r 5 20.40; P , 0.001) (Figure 3). The UACR levels at 12 months remained essentially stable in a subgroup of 52 patients. Using the pathological accepted threshold, 10 patients had a significant change: 7 patients with previously normal values became abnormal, whereas 3 became normal. In contrast, the other 42 patients remained in the same category. The Bland-Altman plot comparing baseline and 12-month values with upper and lower limit (1.96 SD) showed good consistency of data with only three (6%) outliers (Figure 4). A trend to increased differences in MAB was related to MAB mean levels (0.25; 95% CI, 0.09–0.11; P 5 0.003).
DISCUSSION To our knowledge this is the first study reporting a higher prevalence of MAB in patients with stable COPD compared with control subjects who smoked and where both groups had
Figure 2. Geometric median urinary albumin to creatinine ratio (UACR) with percentiles (P25-75) range in smokers with and without chronic obstructive pulmonary disease (COPD) for (A) the entire population and (B) excluding patients with diabetes mellitus and hypertension. The UACR was greater in the patients with COPD.
no known cardiovascular disease. MAB was observed in 24% of the patients compared with 6% of non-COPD control subjects. The MAB levels were inversely related to PaO2 and positively with the A-PaO2 gradient and the PaCO2 but not to other lung function parameters or the BODE index. The MAB levels appeared stable over 1 year of observation. Only three previous studies have described the prevalence of MAB in patients with COPD (22–24). In the first study, the level of MAB was measured in 25 patients during exacerbations. It was detected in 56% of them at admission and in 28% at discharge, compared with 4% in control subjects. MAB was associated with hypoxemia but not with the FEV1 (22). In the second study, the patients were evaluated during exacerbations and the authors reported an association between MAB and the presence of respiratory failure. However, spirometric measurements were not performed (23). In the third study, 33 patients with stable COPD, 26 patients with exacerbation, and 16 healthy subjects were assessed. The level of MAB was significantly increased only in the group with exacerbation. However, in the stable COPD group, the level of MAB was double that of the control group (24). These results suggest that MAB is frequent in COPD and that it appears to increase during exacerbations. In this larger cohort of stable patients with COPD, the prevalence of 24% of MAB is similar to the 25% observed in patients with diabetes (35). The association with chronic renal failure was lower than that previously reported in elderly patients with COPD (36). We did not find differences in the history of hypertension and diabetes between patients with COPD with and without MAB. However, patients with MAB had a slightly higher level of systolic arterial pressure (Table 3) of unknown
Casanova, de Torres, Navarro, et al.: Microalbuminuria and COPD TABLE 2. BASELINE CHARACTERISTIC OF THE PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND MICROALBUMINURIA (URINARY ALBUMIN TO CREATININE RATIO >20 mg/g IN MEN OR >30 mg/g IN WOMEN) AND PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE WITHOUT MICROALBUMINURIA Patients with COPD without MAB (n 5 98)
Patients with COPD with MAB (n 5 31)
P Value
68/30 65 (10) 58 (25) 28 (5) 1.60 (0.68) 61 (20) 30 (31) 70 (10) 40 (47) 17 (20) 41 (5) 16 (19) 29.2 (8.3) 32 (8) 17 (20) 80 (23) 34 (50) 480 (108) 1 (0–4) 1 (0–6) 11 (11)
24/7 67 (9) 58 (22) 28 (6) 1.50 (0.70) 59 (25) 10 (32) 62 (11) 22 (76) 11 (38) 44 (6) 9 (32) 33.5 (9.4) 34 (11) 5 (19) 82 (29) 8 (40) 477 (86) 1(0–4) 1 (0–7) 5 (16)
0.389 0.350 0.980 0.904 0.531 0.762 0.863 0.002 0.006 0.049 0.008 0.133 0.026 0.332 0.911 0.721 0.431 0.875 0.383 0.542 0.533
Sex M/F, n Age, yr Pack-years BMI, kg/m2 FEV1, L FEV1, % FEV1 ,50%, n (%) PaO2, mm Hg PaO2 ,70 mm Hg, n (%) PaO2 ,60 mm Hg, n (%) PaCO2, mm Hg PaCO2 .45 mm Hg, n (%) A-aPO2, mm Hg IC/ TLC IC/ TLC <0.25, n (%) DLCO, % DLCO ,80%, n (%) 6MWD, m Dyspnea, MMRC* BODE Index* BODE Index .3, n (%)
Definition of abbreviations: A-aPO2 5 alveolar-arterial PO2 difference; BMI 5 body mass index; BODE 5 body mass index, airflow obstruction, dyspnea, and exercise performance; COPD 5 chronic obstructive pulmonary disease; IC 5 inspiratory capacity; MAB 5 microalbuminuria; MMRC 5 modified Medical Research Council scale; 6MWD 5 6-minute walk distance; TLC 5 total lung capacity. Data presented as mean (SD) unless otherwise noted. * Median (5th–95th percentile).
clinical significance. The prevalence of reported diabetes mellitus was higher in the COPD group than in control group of smokers, but this was not statistically significant. Furthermore, the difference in the levels of MAB between COPD and control subjects remained significant when patients with diabetes mellitus were excluded. In addition, diabetes mellitus was not independently associated with MAB level in the multivariate analysis in the TABLE 3. BASELINE LABORATORY AND CARDIOVASCULAR RISK FACTORS OF THE PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND MICROALBUMINURIA (URINARY ALBUMIN TO CREATININE RATIO >20 mg/g IN MEN OR >30 mg/g IN WOMEN) AND PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE WITHOUT MICROALBUMINURIA Patients with COPD without MAB (n 5 98) Diabetes mellitus, n (%) Hemoglobin AIc Hypertension, n (%) ACE inhibitors or ARB use, n (%) Systolic arterial pressure, mm Hg Diastolic arterial pressure, mm Hg Statins use, n (%) LDL cholesterol, mg/dl Charlson Index*
20 5.9 33 27 129 75 44 126 1
(20) (1) (33) (29) (15) (11) (34) (33) (0–4)
Patients with COPD with MAB (n 5 31) 8 6.3 9 5 137 80 13 126 1
(26) (1.5) (29) (17) (13) (10) (33) (38) (0–4)
P Value 0.525 0.337 0.631 0.208 0.014 0.065 0.827 0.995 0.762
Definition of abbreviations: ACE 5 angiotensin-converting enzyme; ARB 5 angiotensin II receptor blocker; COPD 5 chronic obstructive pulmonary disease; LDL 5 low-density lipoprotein; MAB 5 microalbuminuria. Data presented as mean (SD) unless otherwise noted. * Median (5th–95th percentile).
1007 TABLE 4. RELATIVE RISK OF THE PRESENCE OF MICROALBUMINURIA IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE USING MULTIVARIATE LOGISTIC REGRESSION MODELING* INCLUDING AGE, DIABETES MELLITUS, HEMOGLOBIN AIC, HYPERTENSION, SYSTOLIC ARTERIAL PRESSURE, DIASTOLIC ARTERIAL PRESSURE, PaO2, AND PaCO2
PaO2, mm Hg Systolic arterial pressure, mm Hg
RR
95% CI
P Value
0.910 1.034
0.857–0.958 1.011–1.057
,0.001 0.003
Definition of abbreviations: CI 5 confidence interval; RR 5 relative risk. * With constant using backward stepwise method and Wald criteria.
group of patients with COPD. In contrast, the finding of an independent and significant association between PaO2 and MAB is in line with and extends the reported presence of MAB in patients with COPD with exacerbations (22). Interestingly, we observed a relation between MAB and hypoxemia that was stronger than with other cardiovascular risk factors. Several studies have reported a relation between hypoxia and MAB in normal subjects at high altitude (37, 38). The potential mechanism could be an increase in renal capillary permeability due to inflammatory mediators, such as tumor necrosis factor-a, interleukins, and free oxygen radicals. In vitro studies have reported a relation between the glomerular size and intercellular gaps and decreases in arterial PaO2 (39). In our study, most of the patients with MAB had hypoxemia and the highest values (.50 mg/g) of MAB were observed in patients with PO2 levels less than 70 mm Hg. Nevertheless, some patients with hypoxemia did not show MAB, suggesting that other factors, such as genetic susceptibility to oxidative stress, may play an important role (40). The development of anorexia in patients with COPD and in normal subjects exposed to high altitude support the importance of hypoxia on metabolic regulatory mechanisms through hypoxia inducible factor 1 (41). An equally likely explanation is that endothelial dysfunction may be directly implicated in the pathogenesis of COPD. Endothelial cells could be directly affected by the cigarette smoke products and this might be associated with reactivity to hypoxic stimulus, thereby altering ventilation-perfusion matching (VA/Q) and resulting in hypoxemia (42). In fact, as suggested by the work of Rodriguez-Roisin and coworkers (43), this vascular dysfunction could explain the substantial increase of A-aPO2 due to VA/Q mismatch in GOLD stage I and the modest increase of VA/Q in more severe stages of the disease. In addition, hypoxemia could result in up-regulation of vascular endothelial growth factor, reduced expression of endothelial nitric oxide synthase, and increase in oxidative stress, which in turn might amplify and perpetuate the dysfunction. The cross-sectional nature of this study does not allow us to establish a causal relationship between hypoxemia and MAB. Results of numerous studies demonstrate the value of MAB as a clinically relevant tool for the identification of generalized endothelial dysfunction and detection of patients at risk for the development of end-organ damage and cardiovascular disease (12–14, 19). Therefore, MAB might help in the identification of a subgroup of patients with COPD at increased cardiovascular risk and potential adverse prognosis. In fact, previous studies have shown the predictive value of MAB in the development of acute respiratory failure and multiple organ failure in ICU patients (44). This opens the possibility of assessing new potential therapeutic strategies, such as statins and blockers of the reninangiotensin system, for these patients. The effects of these agents on reduction of the MAB could be useful in decreasing cardiovascular morbidity and mortality in patients with COPD (20, 45).
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Figure 3. There was an inverse association of the PaO2 and microalbuminuria (MAB) in the patients with chronic obstructive pulmonary disease (r, 20.40, P , 0.001).
We observed no association between MAB and the spirometric severity of COPD. In fact, recent studies suggest that anatomic emphysema is more closely related to impaired vascular function than the degree of airways obstruction. Unfortunately, we did not measure the percentage of emphysema with CT but in the studies where the arterial stiffness and endothelial dysfunction were evaluated (7, 8), the PaO2 was not measured (7) or the subjects with severe hypoxemia were excluded (8).
One important finding in our study is the consistency and reliability of the MAB signal. In fact, only three outliers were detected in 52 patients retested after 1 year. The higher mean values of MAB in the second measurement could be explained by progressive endothelial dysfunction in these patients. Long-term follow-up exploring this hypothesis needs to be implemented. There are several limitations of this study. The first is the relatively small sample size of the control group (smokers without
Figure 4. Bland-Altman plot reproducibility of microalbuminuria (MAB) levels between two measurements. The MAB level remained stable over the mean 12-month follow-up period. UACR 5 urinary albumin to creatinine ratio.
Casanova, de Torres, Navarro, et al.: Microalbuminuria and COPD
COPD) and this could prevent the detection of differences in some parameters, such as family history of diabetes. However, the prevalence of MAB in the control group is similar to the prevalence reported in large population studies (19). Second, the control group was younger than the patients with COPD and it could be argued that this difference could help explain the difference in MAB prevalence. Although possible, this is unlikely because the difference in the prevalence of MAB between patients with COPD and control smokers was the same in the subgroup analyses of the subjects with similar age than in the whole cohort. Furthermore, the number of pack-years smoked was not associated with the levels of MAB. In addition, neither age nor pack-years were associated with the level of MAB in the multivariate analyses of the COPD group. Third, in this study we did not compare the MAB with other biomarkers, such as CRP. However, CRP is not a biomarker that has proven useful in COPD and therefore is not a comparator gold standard. Fourth, few women were included in this study and this makes impossible any evaluation of possible sex differences in MAB. The limited number of women was not by design, because we offered the opportunity to join the study independent of sex. Finally, it is possible that sample size may not allow the detection of significant differences in lung function between patients with and without MAB (type II error). However, our study is the largest to date and is in agreement with the smaller studies that reported no association between MAB and lung function. It is interesting that PaO2 and not the degree of airway obstruction has shown the strongest link to telomere shortening (associated with atherosclerosis) in patients with COPD (46). In summary, in patients with stable COPD without known cardiovascular disease, we have shown a high prevalence of MAB, which was associated with hypoxemia independent of traditional risk factors, such as cigarette smoking, hypertension, and diabetes. The presence of MAB remained stable over 1 year of observation. The determination of MAB is simple, inexpensive, and noninvasive. As such, it could be a promising biomarker to identify patients with COPD at increased cardiovascular risk. Longitudinal studies in different settings with larger populations are needed to evaluate the practical role of MAB in patients with COPD. Author Disclosure: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
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