Introduction
Bronchial asthma is a common chronic disease of the respiratory system that affects ∼300 million people worldwide. It is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by a history of respiratory symptoms such as wheezing, shortness of breath, chest tightness, and cough, which vary over time and in intensity, together with variable expiratory airflow limitation [1]. Chronic kidney disease (CKD) is a growing public health problem. The course of CKD is variable. To date, several risk factors have been identified for the development and progression of CKD, such as older age, obesity, cigarette smoking, diabetes, and hypertension [2]. However, CKD research is a relatively recent field, with most of the significant findings published within the past 10 years. Therefore, in addition to well-known risk factors, there might be other previously underestimated or unrecognized risk factors not yet discovered [3]. In addition, chronic renal failure (CRF) may be associated with normal serum creatinine concentration, a condition known as unrecognized or concealed CRF. It is diagnosed by glomerular filtration rate (GFR) less than 60 ml/min/1.73 m2 [4].
Study questions
- Does bronchial asthma constitute a risk for the development of CKD?
- What are the factors associated with the development of CKD among asthmatic patients?
Study objective
The objectives of the present study were as follows:
- To determine the frequency of CKD among asthmatics compared with nonasthmatics.
- To determine factors associated with CKD among asthmatic patients.
Patients and methods
The present study was an analytical, cross-sectional study conducted between January 2015 and September 2016.
Study population
A total of 118 asthmatic patients (the group assumed to have a risk for development of CKD) and 118 healthy individuals (the group assumed not having a risk for development of CKD) matched for age (within 5 years age group) and sex with the asthmatic patients were included. Healthy individuals were chosen among persons attending the outpatient clinics (e.g. ophthalmology, ENT), patient relatives, and hospital employees.
All asthmatic patients were recruited from the Chest Diseases Outpatient Clinic, Al-Zahraa University Hospital, who had symptoms of airflow limitation and fulfilled lung function criteria set out by Global Initiative for Asthma (GINA) [1] for diagnosis of bronchial asthma [typical symptoms and spirometric evidence of airflow obstruction with positive bronchodilator reversibility test at the time of diagnosis in the form of an increase in forced expiratory volume in the first second (FEV1) more than 200 ml or more than 12% of baseline value 15 min after four puffs of inhaled salbutamol (400 μg) given using a metered-dose inhaler].
Asthma control was categorized as well controlled and not well controlled (partially controlled and uncontrolled) in agreement with GINA guidelines [1]. In particular, levels of asthma control were defined depending on the presence/absence of daytime symptoms, limitations of activities, nocturnal symptoms/awakening, need for reliever/rescue treatment, and FEV1 results.
Exclusion criteria
Patients having the following diseases were excluded from the study − chronic obstructive pulmonary disease (COPD), bronchiectasis, pulmonary embolism, left ventricular systolic or diastolic dysfunction, malignancy, systemic autoimmune disorders, infectious diseases, recent surgery, and endocrine, hepatic, or renal disease (or raised serum creatinine). In addition, smokers were excluded from both the study groups (asthmatics and healthy individuals).
All study individuals were subjected to the following:
- Complete history taking: age, sex, occupational exposure, asthma duration, current asthma medication, and number of acute attacks during the last year, family history of allergy, and physical examination.
- Partial O2 pressure (PaO2, mmHg) was analyzed by a ‘rapid lap analyzer 248’ apparatus (USA) and plain chest radiography posteroanterior view (for patients).
- Laboratory investigations: routine investigation included complete blood analysis, serum creatinine, and liver enzymes.
- Creatinine levels were analyzed using Jaffe’s method on a Cobas c 311 auto-analyzer system, using commercial kits supplied by Roche Diagnostics (Roche Diagnostics GmbH, Mannheim, Germany).
- Serum creatinine was measured by the standardized Jaffe method in all laboratories of the participating centers. The cutoff used for serum creatinine was 1.26 mg/dl in men and 1.04 mg/dl in women [5]. Patients were categorized according to their renal function as having normal renal function (GFR≥60 ml/min/1.73 m2), concealed CRF (normal serum creatinine and GFR<60 ml/min/1.73 m2), or overt CRF (increased serum creatinine and GFR<60 ml/min/1.73 m2) [6].
- Ventilatory function test was carried out using Spirosift spirometry 5000 (Fukuda Denshi, China). Inhaled short-acting bronchodilators, long-acting β-agonists, and sustained-release theophylline were withheld for 6, 12, and 24 h, respectively, before the test. The following indices were recorded: forced vital capacity (FVC), FEV1, FEV1/FVC, forced expiratory flow rate 25–75%, and peak expiratory flow rate (PEFR). Spirometric indices were calculated using the best out of three technically satisfactory trials in accordance with the American Thoracic Society [7]. Asthma severity was determined according to GINA [1] (well controlled, partially controlled, and uncontrolled)
- Estimated glomerular filtration rate (eGFR) was calculated using the four-variable Modification of Diet in Renal Disease study equation, including age, sex, race, and serum creatinine [8]. The estimation was performed using a computer with a GFR calculator, applying the following formula [9]:
Data management and statistical analysis
- Data collection was carried out using a questionnaire including all the required variables (sociodemographic, examination, investigation results, etc.) for both the study groups.
- Data were coded, entered, and cleaned using the statistical package for social science, version 20 (SPSS Inc., Chicago, Illinois, USA).
- Some variables were recorded from quantitative variables to be categorical (e.g. disease duration and CKD classification based on the GFR).
- Data analysis was performed in the form of univariate analysis: descriptive statistics (frequencies and percentages for qualitative data and mean±SD for quantitative data). For bivariate analysis, cross-tabulation was used. The χ2-test and Fisher’s exact test were used to test the difference between the proportions of qualitative data. The Student t-test was used to compare the mean of two different groups. A correlation test was performed between GFR and other quantitative variables (age, disease duration, etc.). For multivariate analysis, linear regression was used for factors affecting the GFR. A binary logistic regression analysis was carried out to determine predictors of CKD among patients with bronchial asthma.
- Statistical significance was considered at a P-value less than 0.05 for all statistical tests.
Ethical considerations
All patients gave their informed consent before enrollment after clarification of the study objectives. The study protocol was approved by the Al-Azhar Ethical Committee Board. Privacy of participants was maintained throughout the study. Confidentiality of data for all the study groups was well maintained. Persons with CKD according to GRF were contacted, informed, and managed through referral to the Nephrology Department at Al-Zahraa University Hospital.
Results
Out of 118 persons in each study group, 103 (87.3%) were females and 15 (12.7%) were males. The mean age was 42.5±10.9 among asthmatic patients versus 40.7±11.8 among healthy individuals, with no statistically significant difference. BMI was significantly lower in the asthmatic group than in the healthy group (26.4±4.3 vs. 28.6±5.8, respectively). GFR was significantly lower in the asthmatic group compared with healthy individuals (92.6±19.6 vs. 100.8±12.5, respectively). Development of CKD was higher among asthmatic patients than among healthy individuals (17.4 vs. 0.8%, respectively) with very high statistically significant difference (Table 1). The percentage of well-controlled asthmatic persons was higher among females than among males (41.7 vs. 26.7%, respectively), but this difference was not statistically significant. Well-controlled asthmatic patients were significantly younger compared with uncontrolled asthmatic patients (38.7±10.8 vs. 45.0±10.3 years, respectively). In addition, disease duration was significantly longer among uncontrolled patients than among controlled patients (19.3±7.7 vs. 15.6±6.9 years, respectively). The percentage of controlled patients was significantly higher among those with disease duration less than 20 years than those with long duration of at least 20 years (48.2 vs. 18.2%, respectively). There was no statistically significant difference between both groups regarding BMI. GFR was higher in the well-controlled group than in the uncontrolled group (96.3±18.1 vs. 90.1±20.3), but this difference was statistically insignificant. Moreover, the percentage of CKD was higher in the uncontrolled group than in the well-controlled group (58.4 vs. 41.6%, respectively), but the difference was statistically insignificant (Table 2).
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Table 1: Comparison between the asthmatic group and the control group regarding sex, age, BMI, and glomerular filtration rate
Table 2: Comparison between well-controlled and uncontrolled asthmatic patients regarding sex, age, disease duration, BMI, glomerular filtration rate, and chronic kidney disease
Development of CKD was higher among males than females (15.5 vs. 6.7%, respectively), but this difference was statistically insignificant. Patients with CKD were significantly older than those without CKD with a mean age 52.9±3.7 versus 40.7±10.7 years, respectively. Occurrence of CKD was significantly higher among those with asthma for at least 20 years than those with asthma for less than 20 years (45.5 vs. 2.4%, respectively). Development of CKD was higher in the uncontrolled asthmatic group than in the controlled group (16.9 vs. 10.6%, respectively), but the difference was statistically insignificant. BMI was significantly higher among persons with CKD than those without CKD (30.3±5.4 vs. 25.8±3.7, respectively). In addition, all parameters of pulmonary function were significantly higher among asthmatic patients with no CKD than those with CKD (Table 3). GFR was negatively correlated to age, BMI, and disease duration with high statistical significance. On the other hand, GFR was positively correlated to all parameters of pulmonary function (FVC%, FEV1%, FEV1/FVC, and PEFR%) and PaO2 with high statistical significance (Table 4). Multivariate analysis showed that significant determinants of GFR among asthmatic patients were disease duration and PaO2 (Table 5 and Figs. 1 and 2). Significant predictors for the development of CKD among asthmatic patients were longer disease duration and higher BMI, whereas high PaO2 was protective for the development of CKD (Table 6).
Table 3: Factors affecting the development of chronic kidney disease among asthmatic patients
Table 4: Correlation between glomerular filtration rate and other parameters among asthmatic patients
Table 5: Multivariate analysis of factors affecting glomerular filtration rate among asthmatic patients
Figure 1: Correlation between partial O2 pressure (PaO2) and glomerular filtration rate (GFR) among asthmatic patients.
Figure 2: Correlation between glomerular filtration rate (GFR) and disease duration among asthmatic patients.
Table 6: Multivariate analysis of factors affecting the development of chronic kidney disease among asthmatic patients
Discussion
CKD is a growing public health problem with well-established risk factors. Other contributing factors, however, remain to be identified [10]. Systemic inflammation in asthma plays a significant role in the development of other diseases [11]. The course of CKD is variable. To date, several risk factors have been identified for the development and progression of CKD such as older age, obesity, cigarette smoking, diabetes, and hypertension [2]. Growing asthma, which is another type of airway inflammation, is also characterized by an abnormal inflammatory response of the lungs to noxious or sensitized particles and gases. Consequently, we speculate that asthma might also be associated with CKD [11].
In this study, GFR was significantly lower in asthmatic than in healthy individuals, and development of CKD was higher among asthmatic patients than in healthy individuals with a very high statistically significant difference. A growing number of studies over the last two decades have shown that airway inflammation and obstruction are important contributors to other common causes of morbidity and mortality. Patients with COPD are more than two times at risk for cardiovascular mortality [12]. A recent study showed that both moderate and severe COPD were independently associated with an increased risk of long-term mortality in patients with CKD [13].
This is in agreement with Liu et al. [14] and Huang et al. [15] who found that patients with asthma were more likely to have CKD compared with controls.
Asthma has been generally considered to be a type of chronic airway inflammation, and proinflammatory cytokines have been shown to play a central role in the pathogenesis of asthma. However, the inflammation is not only restricted to the lungs, but also extends systemically [16]. Two studies have shown increased levels of biomarkers of systemic inflammation (C-reactive protein and interleukin-6) in asthmatic groups [17].
This systemic inflammation could have a significant effect on initiating and aggravating other disease processes, including kidney disease [16], in which the cytokines and inflammatory mediators associated with asthma play a modifying role in renal disease. For example, interleukin-6 has the potential to modulate T-helper 2 immunity in asthma, which is also independently associated with kidney dysfunction in participants aged 65 years and above, as reported in the Cardiovascular Health Study [18].
Tumor necrosis factor-α (TNF-α), a mediator of the acute-phase reaction of early inflammatory response, is considered to be a multifunctional cytokine involved in airway inflammation [19] and also increases airway contractility in asthma [20]. In the kidney, TNF-α contributes to the chronic inflammation that often precedes interstitial matrix deposition and is also implicated in obstruction-induced renal injury [21]. Serum levels of TNF-α have been shown to be elevated in patients with CKD, with a general increase with declining renal function [22]. A recent study suggested that TNF-α inhibition could reduce renal injury in DOCA-salt hypertensive rats [23]. Likewise, leptin levels are elevated during asthma, and also increased in patients with end-stage renal disease, suggesting that this factor may be relevant to systemic inflammation [24].
In our study, GFR was higher in the well-controlled group than in the uncontrolled group; this is in agreement with Liu et al. [14] who also reported that a higher proportion of patients with not well-controlled and persistent asthma developed proteinuria (as an early indicator of renal dysfunction) compared with patients with at least well-controlled and remission asthma. In addition, compared with patients with at least well-controlled asthma, patients with asthma that was not well controlled had a significantly higher frequency of reduced eGFR. The prevalence of reduced eGFR also differed significantly between groups that were classified by history of asthma and stage.
The present study revealed that BMI was significantly higher among persons with CKD than those without CKD. Obesity is a modifiable risk factor for many chronic diseases including cardiovascular disease, diabetes mellitus, osteoporosis, asthma, and CKD. The association between obesity and higher prevalence of asthma has previously been reported in a number of studies. A recent study demonstrated that obesity is one of the risk factors for difficult-to-treat asthma [25]. In CKD, obesity is a key risk factor and is implicated in the development of focal segmental glomerulosclerosis and glomerulomegaly. Inflammation and oxidative stress were two key risks in obesity-related glomerulopathy [26].
Our study reported that occurrence of CKD was significantly higher among those with asthma duration of at least 20 years than those with asthma for less than 20 years, and GFR was negatively correlated to disease duration with high statistical significance. This is agreement with Liu et al. [14] who reported that the proportion of the patients who developed proteinuria was significantly higher among patients with an asthma history of more than 20 years than those with an asthma history of 20 years or less.
GFR was negatively correlated to age. In addition, most researchers reported that older patients have an increased risk of developing CKD [27].
We also reported that GFR was positively correlated with all the parameters of pulmonary function (FVC%, FEV1%, FEV1/FVC, and PEFR%) and PaO2; this is in agreement with Liu et al. [14], who demonstrated that persistent asthma is associated with an increased risk for CKD. The risk was independent of potential confounding factors such as age, sex, hypertension, diabetes, BMI, and personal smoking habits. Moreover, the increased risk for CKD was associated with an increased number of asthma traits, even after adjusting for demographic factors and additional adjustment.
In addition, the risk did not substantially differ by age, sex, hypertension, diabetes, BMI, obesity, and personal smoking habits. The increased risk for reduced eGFR was observed among individuals with persistent-stage asthma in unadjusted analyses. After adjustment for demographic factors and additional adjustment for hypertension, diabetes, BMI, obesity, and personal smoking habits, the increased risk for reduced eGFR remained significant [15].
In addition, hyperventilation, hypoxemia, and acidosis caused by acute exacerbation and severe persistent asthma tend to result in kidney damage [28]. The potential mechanism underlying these processes could be an effect on renal capillary permeability due to inflammatory mediators such as TNF-α and interleukins [29].
Several studies have reported microalbuminuria to be associated with hypoxia in normal persons and COPD patients [30]. In-vitro studies have shown a relationship between glomerular size and decrease in arterial PaO2 [31].
The associated inflammation that occurs in asthma could be a responsible factor in the increased rate in kidney disease. Future studies should be directed to elucidate the mechanisms underlying the association between asthma and CKD as well as investigate the implication that improvement of asthma control may reduce the risk for CKD. These findings have important clinical and public health implications because asthma and CKD are common chronic diseases.
Study limitations
- Proteinuria could not be determined among asthmatic patients and healthy individuals.
- Exclusion of many other asthmatic patients because of associated comorbidities.
- Economic burden of investigations that limited the number of persons in both groups.
Recommendation
- Regular assessment of PaO2 among asthmatic patients and maintaining O2 supply.
- Regular follow-up of kidney functions through GFR and proteinuria test among asthmatic patients, especially those with long disease duration and/or poor control of asthma.
- Further studies, case–control and cohort studies, with larger samples to obtain strong evidence regarding the association between bronchial asthma and CKD.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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