Prevalence of chronic kidney disease in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis

Background The incidence and prevalence of chronic kidney disease (CKD) continue to rise worldwide. Increasing age, diabetes, hypertension, and cigarette smoking are well-recognized risk factors for CKD. Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation leading to airway obstruction and parenchymal lung destruction. Due to some of the common pathogenic mechanisms, COPD has been associated with increased prevalence of CKD. Methods Systematic review of medical literature reporting the incidence and prevalence of CKD in patients with COPD using the Cochrane Collaboration Methodology, and conduct meta-analysis to study the cumulative effect of the eligible studies. We searched Medline via Ovid, PubMed, EMBASE and ISI Web of Science databases from 1950 through May, 2016. We included prospective and retrospective observational studies that reported the prevalence of CKD in patients with COPD. Results Our search resulted in 19 eligible studies of which 9 have been included in the meta-analysis. The definition of CKD was uniform across all the studies included in analysis. COPD was found to be associated with CKD in the included epidemiological studies conducted in many countries. Our meta-analysis showed that COPD was found to be associated with a significantly increased prevalence of CKD (Odds Ratio [OR] = 2.20; 95% Confidence Interval [CI] 1.83, 2.65). Study limitations: Studies included are observational studies. However, given the nature of our research question there is no possibility to perform a randomized control trial. Conclusions Patients with COPD have increased odds of developing CKD. Future research should investigate the pathophysiological mechanism behind this association, which may lead to better outcomes. Electronic supplementary material The online version of this article (doi:10.1186/s12890-016-0315-0) contains supplementary material, which is available to authorized users.


Background
Chronic kidney disease (CKD) is a major public health problem in the United States, with rising incidence and prevalence of kidney failure, with poor outcomes and high cost. There is an even higher prevalence of earlier stages of CKD. According to the Third National Health and Nutrition Examination Survey (NHANES III), it was estimated that 6.2 million people (3% of total US population) above the age of 12 years had a serum creatinine above 1.5 mg/dl and 8 million people had a glomerular filtration rate (GFR) <60 ml/min/1.73 m 2 The majority of these people are greater than 65 years of age (5.9 million).
Diabetes, hypertension and cardiovascular disease are associated with greater prevalence of CKD [1,2]. In addition, CKD has a complicated interrelationship with these diseases. As per United States Renal Data System (USRDS data), prevalence of stage 3 CKD has been increasing. Although the prevalence of hypertension (HTN) did not rise, the incidence of diabetes mellitus (DM) has increased 4 fold from 1980 to 2014 [3]. Studies have reported that CKD is an independent risk factor for cardiovascular disease [4]. In recent years, additional causes of CKD have been recognized such as unrecovered acute kidney injury (AKI) [5,6] and use of proton pump inhibitors (PPIs) [7,8], In this manuscript we analyze the association of CKD with COPD using the limited data available… Several studies have identified COPD as part of a systemic inflammatory syndrome [9][10][11][12] and reported on the association of comorbidities like lung cancer [13], osteoporosis [14], progression of atherosclerosis [15], and CKD. This systematic review was performed to assess the association of COPD with CKD.

Eligibility criteria
We included prospective and retrospective observational studies that reported the prevalence of CKD in patients with COPD when compared to those without COPD. Most of the studies established the diagnosis of COPD using Spirometry or ICD-9 codes obtained from their medical records while others were based on history or physician diagnosed COPD. Prevalence of CKD in the majority of the studies was reported based on eGFR obtained from laboratory data. We only included studies that reported data on adult populations.

Search strategy
In January 2016, we electronically searched PubMed, Medline (1950 onwards; access via Ovid), EMBASE (all years; access via Ovid) and Web of Science using a detailed search strategy with search terms described below and in Additional file 1. After initial detailed discussion of the aim of the study, the search strategy was outlined by the authors. Search terms used for COPD were: 'COPD' , 'chronic obstructive pulmonary disease' , 'emphysema' , 'chronic bronchitis'. Search terms used for CKD were: 'chronic kidney disease' , 'CKD' , 'ESRD' , 'end stage renal disease' , 'renal insufficiency' , 'renal failure'.
Inclusion criteria: We included all prospective and retrospective observational studies reporting the prevalence of CKD in patients with COPD compared to those without COPD; there were no restrictions on language of publication.
Exclusion criteria: We excluded studies that did not report the association of CKD with COPD; those that were not focused on the association of CKD with COPD; studies that did not have appropriate methodological study design of comparison groups; studies with data which was incompletely recorded; and those involving pediatric populations.
We reviewed keywords and related studies. From using the selected studies, we proceeded further in the literature search looking for "related articles" in PubMed. References of the included studies were manually searched to ensure inclusion of all related articles.

Selection process
Two reviewers independently reviewed the titles and abstracts of the citations resulting from the search using a standardized screening guide. Full text was obtained for the articles which were thought to be eligible by at least one of the reviewers.. Each reviewer reviewed these full texts independently to judge their eligibility to be included in our review. Disparities between the two reviewers about which studies should be included were discussed and resolved by a third reviewer.

Data abstraction
Data was independently extracted from the included studies by two reviewers (SG and SGK) using a standardized and pilot-tested form for data abstraction. Any differences in extracted data were discussed by the reviewers, and if not resolved, by discussion with a third reviewer. The pilot-tested form included study design, method used to diagnose COPD and CKD, population, methodological characteristics of the study, and the reported results. We recorded the effect measures derived from the regression models that adjusted for the maximum number of covariates. We rated the overall quality of evidence for each outcome using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach [16].

Data analysis
The kappa statistic was calculated to determine the agreement between the two reviewers of the full texts of the studies for inclusion eligibility. Meta-analysis was performed from the studies that reported the prevalence/incidence of CKD in patients with COPD compared to patients without COPD. In studies that did not report actual number of events, other available data (such as percentages) was used to calculate the number of events for the evaluated outcomes. For each outcome, we pooled the odds ratios (OR) of eligible studies using the generic inverse variance and the random effects model in Review Manager Version 5.3. The random effects model was used as the included studies evaluated different patient populations. We measured homogeneity across study results using the I 2 statistic. We examined possible publication bias using inverted funnel plots.

Results
Our extensive electronic database search of databases in January, 2016 resulted in 7583 articles. A flow diagram with detailed outline of literature search is provided in Additional file 2. After detailed review of the articles, our literature search resulted in 17 studies related to the topic of our research. Manual search for related articles helped identify an additional study that was recently published and did not have a PubMed ID [17]. Another study was published in April 2016 while we were in the process of submission for publication [18]. As a result, we included 19 articles related to our topic of interest.
Nine of these studies reported the prevalence of CKD in patients with COPD compared to those without COPD [17][18][19][20][21][22][23][24][25][26]. We reported a detailed review of these studies with data extraction in Table 1 and we included the results reported in these studies in a meta-analysis to estimate the cumulative effect. The remaining 10 studies did not meet inclusion criteria for meta-analysis [27][28][29][30][31][32][33][34][35]. A detailed review of these articles is reported in Table 2. Eight of these 10 studies have been excluded since they are longitudinal studies that reported the prevalence of CKD in a cohort of patients with COPD [18,[27][28][29][30][32][33][34]. One of the studies has been excluded due to the study design and since the data could not be used for analysis [31]. One other study was excluded due to use of non-standardized method to assess the prevalence of CKD and therefore did not meet criteria to be included in the systematic review [35]. The reviewers had very good agreement on study eligibility (kappa = 0.983). Using GRADE approach [16], the quality of evidence from the studies included in our review was found to be moderate to low.
Results from meta-analysis ( Fig. 1) showed statistically significant higher prevalence of CKD among COPD patients compared to controls without COPD; OR 2.20 [95% CI: 1.83, 2.65]. I 2 value of 82% indicates minimal heterogeneity among the studies included in the analysis. Funnel plot of the included studies revealed lack of publication bias (Fig. 2).
The study periods of almost all the studies were in the last 2 decades except one study [30]. Three of the 9 studies included in meta-analysis utilized nationally representative samples in their respective countries [22,24,25]. Only 2 studies reported data on hospitalized patients [19,26] while the remaining 4 studies included patients from outpatient settings [17,20,21,23]. Of the 10 studies that were excluded from the metaanalysis, six studies reported data on hospitalized patients [18,[27][28][29][30]34] Patient population included was aged 40 years or older. Studies included in the meta-analysis had similar gender representation with male participant rates reported from 40% to 65% except one study that reported 83% male participation [17]. Nine of the 10 studies that were not included in the meta-analysis but were included in the systematic review reported predominant male participation ranging from 80% to 98% [18,[27][28][29][30][31][32][33][34].
Of the studies included in meta-analysis, only one study analyzed prevalence of CKD in COPD and control groups based on gender [24]. Van Gestel et al. analyzed the association between prevalence of CKD and severity of COPD [26]. Therefore sub-group analysis could not be performed for prevalence based on gender and severity of COPD.
The reported diagnostic methods and definitions for COPD and CKD were uniform across all the included studies. The value of eGFR reported under laboratory data was used to define CKD in most of these studies. Matching was performed in control group selection in 3 of the 9 studies included in the meta-analysis [19,21,23]. All the included studies performed adjustment in analysis for the identified confounding variables.

Discussion
Our meta-analysis validated previously published results showing a significant increase in prevalence of CKD in patients with COPD compared to patients without COPD. To our knowledge, this is the first meta-analysis conducted on this topic.
Advancing age, diabetes, hypertension, body mass index (BMI), and cigarette smoking have previously been identified as risk factors for new-onset kidney disease [36]. Advancing age, history of asthma, severe respiratory problems in childhood, passive smoking, and exposure to biomass fuel for heating were identified as risk factors for COPD in never-smokers whereas increasing age, history of asthma, and severe respiratory problems in childhood, increasing lifetime exposure to cigarette smoking were identified as independent risk factors for development of COPD in ever-smokers [37]. Many studies have reported on the high prevalence of CKD in COPD patients across different populations and our meta-analysis validated these previously published results. Moreover, all the studies included in our analysis adjusted for co-variates including age, gender, BMI, and smoking status and this allowed for drawing a conclusion on the independent association of CKD with COPD.
The mechanism by which COPD potentiates the development of CKD remains unclear. Several hypotheses have been put forward. It might be related to the fact that COPD is mainly a disease of the elderly population who have comorbidities such as DM, HTN and CAD, known risk factors associated with CKD. COPD has been associated with systemic inflammation [9][10][11][12]. Proinflammatory cytokines, especially tumor necrosis factor-alpha (TNF-α), play an important role in inflammation [38,39], and have been shown to increase endothelial inflammation and atherosclerosis. This inflammation is also potentially related to development of diabetes, muscle wasting, and kidney disease. In a meta-analysis of observational studies, COPD was associated with increased serum concentration of several   The study population was surveyed to estimate the prevalence of a set of 23 diseases in patients with COPD compared to patients without COPD. Self-reported renal disease was included in general and no specifications on chronic kidney disease or renal failure was surveyed. Renal disease was reported 0.3% in patients with COPD compared to 0.2% in non-COPD patients inflammatory mediators [40]. This association can be explained in part by smoking. COPD is associated with microalbuminuria and in hypoxemic and hypercapnic patients effective renal flow was found to be reduced. These changes may be reflective of increased renin-angiotensin system activity seen in COPD patients. In the Multi-Ethnic Study of Atherosclerosis cohort, Harris et al. found an inverse relation between FEV1 and FVC with urinary albumin excretion and urine albumin to urine creatinine ratio [41]. This finding suggests that systemic microvascular injury may contribute to development of CKD in COPD patients.
Medical management of COPD may contribute to the development of CKD. Mapel et al. [23] showed that COPD patients were more likely to be on potentially nephrotoxic medications than controls. This includes recurrent use of antibiotics, as well as PPIs and certain cardiovascular drugs. Our study highlights the high prevalence of CKD in COPD patients and draws attention to the clinical implications.
Our study has a few limitations. First and foremost, we included observational studies in this systematic review and meta-analysis. Observational studies, inherently, depict associations and aid in hypothesis-making but do not establish cause and effect relationships. Additionally, we could not perform subgroup analysis to estimate the differential prevalence of CKD in relation to the severity of COPD that would have otherwise contributed to establishing causal relationship. Another limitation is that although 18 studies were identified to be relevant, only 9 studies could be included in our meta-analysis owing to differences in the study designs and reported results. However, funnel plot analysis did not reveal any publication bias.