REVIEW URRENT C OPINION
Renal and hepatobiliary dysfunction in chronic obstructive pulmonary disease Douglas Mapel
Purpose of review This review examines the associations between chronic obstructive pulmonary disease (COPD) and renal and hepatobiliary diseases, with emphasis on the epidemiology and clinical outcomes, along with current information on pathophysiologic mechanisms and risk factors. Recent findings Glomerular filtration, sodium retention, and waste excretion are abnormal in COPD and sensitive to hypoxemia and hypercarbia, but variably responsive to oxygen administration and angiotensin-converting enzyme inhibition. Newer concepts about the role of hypoxia on the progression of chronic renal failure, and improved understanding about the relationships between COPD, decreased arterial compliance, and renal glomerular injury, are bringing new insights about potential causal mechanisms between COPD and kidney diseases. Other than the well known relationship between cor pulmonale and passive liver congestion, little was known about the relationships between COPD and liver diseases until recent population-based surveys demonstrated that COPD patients have substantially elevated risk for specific hepatobiliary system diseases. Summary Renal complications of COPD are common especially among patients with hypoxemia and hypercarbia. Renal-endocrine mechanisms, tissue hypoxia, and vascular rigidity have roles in the pathophysiology, but understanding of causal relationships is not precise. COPD patients have increased risk for hepatobiliary diseases and asymptomatic elevations of hepatic transaminases, which fortunately have relatively low prevalence. Keywords chronic obstructive pulmonary disease, epidemiology, hepatobiliary, renal
INTRODUCTION Comorbid conditions are a major concern in the management of chronic obstructive pulmonary disease (COPD) patients largely because they are so common. In an analysis of 179 544 COPD patients in the United States, 32.7% had one other major chronic illness, and 39.0% had two or more [1]. However, among the many chronic conditions associated with COPD, there are relatively few published data on the incidence and prevalence of renal and hepatic disease. The reasons for this are not clear, but one explanation is that patients with diagnosed renal or hepatic diseases are usually excluded from clinical trials, and those found to have abnormal elevations in renal function tests or hepatic transaminases during screening are usually excluded. Another possible explanation for the lack of data is that renal and hepatic diseases less commonly cause clinical problems than heart www.co-pulmonarymedicine.com
disease, lung cancer, or other serious COPD comorbidities. Nevertheless, renal and hepatic complications associated with COPD were recognized even before the paradigm of COPD was developed in the early 1960s. Long before the systemic inflammatory mechanisms of COPD were appreciated, the neuroendocrine effects of COPD on renal function and the impact of hypoxemia and hypercarbia on renal blood flow (RBF) were described. The purpose of Lovelace Clinic Foundation, Health Services Research Division, Albuquerque, New Mexico, USA Correspondence to Douglas Mapel, MD, MPH, FCCP, Medical Director, Lovelace Clinic Foundation, Health Services Research Division, 2309 Renard Place SE, Suite 103, Albuquerque, NM 87106-4264, USA. Tel: +1 505 938 9900; e-mail: [email protected] Curr Opin Pulm Med 2014, 20:186–193 DOI:10.1097/MCP.0000000000000024 Volume 20 Number 2 March 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Renal and hepatobiliary dysfunction in COPD Mapel
KEY POINTS COPD is associated with increased risk of both acute and chronic renal failure, which is confirmed in a variety of epidemiologic studies from several countries. COPD with hypoxemia and hypercarbia is associated with sodium retention and reduced glomerular filtration, and is responsive to oxygen therapy but not fully explained by normal renal-endocrine mechanisms. Hypoxic damage to renal tubules and interstitium, along with glomerular damage caused by arterial stiffness, are possible causal mechanisms in the relationship between COPD and renal disease. COPD patients have a moderately increased risk for chronic hepatobiliary diseases, and limited data suggest they also have increased risk factors including alcohol and drug abuse, and increased use of potentially hepatotoxic medications.
this review is to review the relationships between COPD and renal and hepatic diseases, particularly the epidemiologic evidence, pathophysiologic mechanisms, and the factors that affect clinical outcomes.
CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND RENAL DISEASE: EPIDEMIOLOGY Data about the incidence, prevalence, and risk factors for renal disease in COPD come from a range of study designs and populations (Table 1). In the largest population-based analysis of comorbidities in COPD available, Baty et al. [2 ] examined every hospitalization for COPD in Switzerland for calendar years 2002 through 2010, and compared the diagnosed comorbidities among 340 948 COPD admissions (representing 160 317 individual patients) matched by age and sex to 340 948 admissions among non-COPD patients. Comorbidities were classified using the International Classification of Diseases (ICD)-10 coding system. The prevalence of renal disease was significantly elevated in four different categories: acute renal failure (1.80 versus 0.89%), chronic kidney disease (CKD) (4.39 versus 2.13%), CKD – unspecified (4.64 versus 2.25%), and unspecified kidney failure (3.03 versus 1.67%). Although all were highly significant differences (P < 0.001), kidney diseases did not make the top 10 among all COPD comorbidities in terms of prevalence or odds ratio (OR) risk. We conducted a cross-sectional populationbased study of all COPD patients enrolled in one managed care system in the Southwest United States [3 ]. To estimate the increased risk of renal failure &&
&&
and undiagnosed renal insufficiency associated with COPD, we matched each COPD case to three patients without COPD by age and sex. We also examined case–control differences in the use of potentially nephrotoxic drugs. The 2284 cases had approximately twice the incidence of acute renal failure (1.4 versus 0.6%, P < 0.01), and three times the prevalence of diagnosed chronic renal failure (CRF) (2.9 versus 0.8%, P < 0.01), than did the controls. Elevations in renal function tests were also common: 27.1% of the COPD cases had at least one abnormal creatinine level during the study period as compared with 16.7% of controls. Over the 3-year study period, COPD patients averaged 17.6 prescription fills for potentially nephrotoxic agents as opposed to 13.6 fills for controls. However, we did not adjust for differences in other comorbidities such as cardiovascular disease, which we have demonstrated are much higher in this COPD population [4]. Polypharmacy has been identified as a very common problem in other populations of COPD patients with CRF [5]. In a population-based, cross-sectional analysis of comorbidities in a primary care cohort from Madrid, Spain, the prevalence of chronic diseases among 3124 COPD patients was compared with the expected prevalence in this population, adjusted for age and sex [6 ]. Over 90% of COPD patients in this cohort had at least one other chronic condition, most commonly hypertension (52%). CRF was diagnosed in 6.3% overall: 7.1% in men and 3.9% in women. This was a calculated overall prevalence 28% higher than expected, but did not quite reach statistical significance (standardized prevalence ratio 1.28; 95% CI: 0.96–1.59). The prevalence of CRF was also higher among men than women in a registry of 8712 COPD patients from Sweden who had been started on long-term oxygen therapy [7 ]. The prevalence of CRF among women was 1.5% compared with 2.6% in men, with an adjusted OR of 0.58 (P < 0.001). Other comorbidities were also found to have different prevalences by sex, with women having more hypertension, osteoporosis, rheumatoid arthritis, and mental disorders, and men having more arrhythmias, heart disease, and cancer. However, the differences in comorbidities did not explain the better survival among women with COPD in this cohort [hazard ratio 0.73 (95% CI: 0.68–0.77)]. Factors associated with undiagnosed renal failure, defined as a glomerular filtration rate (GFR) less than 60 by the Cockcroft Gault formula, were examined in a cohort of 433 patients in a longitudinal cohort study in Norway [8 ]. Patients who had known renal failure were excluded from this nonrandom survey. In this cohort, women had a higher
1070-5287 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
&
&
www.co-pulmonarymedicine.com
187
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Obstructive, occupational and environmental diseases Table 1. Chronic obstructive pulmonary disease and renal disease: epidemiology and risk factors Reference
Study design
Baty [2 ]
Population-based cohort with 1 : 1 case–control matching for admissions
Mapel [3 ]
Population-based cohort with 1 : 3 case–control matching for all COPD cases
&&
COPD cases (n) Findings 160 317
Based on all hospitalized COPD patients in Switzerland in calendar years 2002–2010. COPD patients had increased odds of acute renal failure (OR 2.00) and all three ICD-10 categories for CRF (OR 1.80–2.10). (P < 0.001 for all comparisons)
2284
COPD patients had twice the incidence of acute renal failure (1.4 versus 0.6%), and three times the prevalence of diagnosed CRF (2.9 versus 0.8%), than did controls. Abnormal renal laboratory values > 2 ULN occurred in 27.1% of COPD cases as compared with 16.7% of controls. COPD patients had 30% more fills for potentially nephrotoxic drugs. (P < 0.01 for all comparisons)
Garcı´a-Olmos [6 ] Population-based cohort
3124
CRF was diagnosed in 6.3% of COPD patients (7.1% of men, 3.9% of women), which was 28% higher than expected in this population (standardized prevalence ratio 1.28; 95% CI: 0.96–1.59)
Ekstro ¨ m [7 ]
Registry of COPD patients on long-term oxygen
8712
CRF occurred in of 0.58 (95% other illnesses diabetes, and
Gjerde [8 ]
Research cohort
433
Undiagnosed renal failure was higher in COPD (6.9%) than a similar comparison group (0.8%), and more common in women with COPD (9.6%) than men (5.1%). Factors associated with renal failure included advanced age, cachexia, use of inhaled steroids, and systemic inflammatory markers
Incalzi [9]
Research cohort
356
COPD had more CRF (22.2% versus 13.4%) and ‘concealed’ renal failure (normal creatinine with reduced GFR) (20.8 versus 10.0%) as compared with similar controls
Research cohort
508
GFR and creatinine level were correlated with the severity of emphysema found on chest CT, but not with the severity of airflow obstruction by spirometry. Hypertension was associated with reduced renal function
&&
&
&
&
Chandra [10 ] &
1.5% of women and 2.6% of men, for an adjusted OR CI: 0.42–0.79). Women also had less prevalence of associated with renal failure, including hypertension, cardiovascular disease
CI, confidence interval; COPD, chronic obstructive pulmonary disease; CRF, chronic renal failure; GFR, glomerular filtration rate; ICD, International Classification of Diseases; OR, odds ratio; ULN, upper limit of normal.
prevalence of reduced GFR (9.6%) than men (5.1%). The overall prevalence of undiagnosed renal failure among COPD patients (6.9%) was much higher than in a similar comparison group (0.8%). Other factors associated with renal disease included advanced age, cachexia, use of inhaled steroids, and serum inflammatory markers including tumor necrosis factor. In a similar study from Italy, 356 elderly outpatients with COPD had a detailed evaluation to examine the prevalence of CRF (abnormal creatinine and GFR) and ‘concealed’ renal failure (normal creatinine but reduced GFR), as compared with an agematched and sex-matched cohort [9]. Each COPD patient was confirmed by pulmonary function testing and underwent a comprehensive physical and laboratory analysis. The prevalence of overt and concealed CRF in patients with COPD was 22.2 and 20.8%, respectively, as compared with 13.4 and 10.0% of controls. In multivariate models, age, diabetes, hypoalbuminemia, and musculo-skeletal diseases were significant correlates of concealed 188
www.co-pulmonarymedicine.com
CRF, whereas age, increased BMI, and diabetes were significantly associated with overt CRF. The relationship between kidney function and the severity of emphysema was examined in a cohort of 508 COPD patients enrolled in a longitudinal clinical study [10 ]. Each patient had a comprehensive clinical evaluation including a computed tomography (CT) scan of the chest, from which the percentage of lung involvement with emphysema was estimated using both radiologists’ impressions and computerized analysis of regional attenuation. In both univariate and multivariate analyses, GFR and creatinine level were correlated with the severity of emphysema, but not with the severity of airflow obstruction by spirometry. The only other clinical factor associated with poor renal function in this COPD population was hypertension, but there was a relatively low prevalence of diabetes and other known renal disease risk factors in this cohort. The authors also examined the hypothesis that right heart failure was a contributing cause of renal insufficiency in COPD, but addition &
Volume 20 Number 2 March 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Renal and hepatobiliary dysfunction in COPD Mapel
of N-terminal pro-brain natriuretic peptide serum levels to the statistical models did not affect the relationship between emphysema and kidney disease.
RENAL DISEASE IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE: IMPACT ON CLINICAL OUTCOMES The relationship between COPD and renal disease and their impact on clinical outcomes can be examined from three perspectives: How does renal failure impact COPD prognosis? How does COPD impact prognosis among persons with chronic renal disease? How do both interact in the outcomes of patients having major procedures? Predictors of mortality among persons hospitalized with a COPD exacerbation were examined in a systematic literature review published by Singanayagam et al. [11 ]. A total of 37 articles, incorporating data from 189 772 study individuals, were included in the meta-analysis. Outcomes were stratified as short-term mortality (90 days or less) and long-term mortality (90 days to 2 years after initial presentation). Renal failure, along with 11 other prognostic factors (age, male sex, low BMI, cardiac failure, confusion, long-term oxygen therapy, lower limb edema, Global Initiative for Chronic Lung Disease stage 4, cor pulmonale, acidemia, and elevated troponin level), was significantly associated with increased short-term mortality. However, renal failure was not among the nine prognostic factors (age, low BMI, cardiac failure, diabetes mellitus, ischemic heart disease, malignancy, forced expiratory volume in 1 s, long-term oxygen therapy, and PaO2 on admission) that were significantly associated with long-term mortality. Renal failure doubled the risk of short-term mortality (OR 1.97; 95% CI: 1.31– 2.94) among the 100 206 persons in the analysis with comparable data, but the point estimate was highly variable across the included studies. Prognostic factors, including risk for hospitalization and mortality, among COPD patients were examined in a prospective study of 288 who were hospitalized for COPD exacerbations and then followed for up to 7 years [12]. Hypertension was the most common comorbidity (64.2%), followed by CRF (26.3%), diabetes mellitus (25.3%), and cardiac diseases (22.1%). However, among the chronic diseases, mortality risk was only related to the presence of cor pulmonale, ischemic heart disease, and lung cancer. Number and length of hospital admissions depended primarily on measures of the severity of lung disease and not on renal failure. Kent et al. [13 ] examined the impact of COPD on a cohort of 769 984 dialysis patients included in &&
&
the US Renal Data System registry between May 1995 and December 2004. The prevalence of diagnosed COPD was 7.5% overall, and increased from 6.7 to 8.1% during the time period. COPD was associated with advanced age, cardiovascular disease, cancer, malnutrition, poor functional status, and current cigarette smoking. Adjusted mortality was significantly increased among the COPD patients [relative risk (RR) ¼ 1.20; 95% CI: 1.18– 1.21], especially the current smokers (RR ¼ 1.28; 95% CI: 1.25–1.32). Persons with COPD were much less likely to be offered kidney transplantation. Renal disease and COPD both have strong associations with atherosclerosis, which led van Gestel et al. [14] to examine how COPD and renal disease affected outcomes among 3371 persons who had undergone peripheral vascular surgery (abdominal aortic repair, carotid endarterectomy, or lower limb arterial reconstruction). CKD was found in 27% and COPD in 39% of this cohort at the time of surgery. COPD was more prevalent in those with CKD (46%) than those without it (36%), and the prevalence of COPD increased with the reduction in GFR. However, there was not a linear association between the severity of airflow obstruction and the risk for CKD at baseline. In long-term follow up, moderate and severe COPD were associated with increased mortality among those with CKD in both univariate and multivariate analyses. Risk factors for acute postoperative renal failure were examined in a prospective case series of 769 patients who underwent cardiac surgery in one academic medical center in Brazil [15]. Seventy-eight patients (10% of cohort) developed renal failure postoperatively, 18 of whom required dialysis. The baseline prevalence of diagnosed COPD was only 4.3%, but COPD patients had four times higher risk of developing renal failure (adjusted OR 4.11; 95% CI: 1.63–10.4).
MECHANISMS OF RENAL MALFUNCTION AND INJURY IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE Problems with abnormal sodium excretion and water retention were noted among patients with chronic bronchitis over half a century ago, particularly if they had chronic hypoxemia or hypercapnia [16]. Initially, this was attributed to the consequences of cor pulmonale, which reduces RBF and GFR, increases aldosterone levels, and may also result in abnormal secretion of antidiuretic hormone [17,18]. However, subsequent research demonstrated that renal-endocrine abnormalities did not adequately explain renal malfunction in COPD. We first review the renal hypoxia, hypercapnia, and
1070-5287 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-pulmonarymedicine.com
189
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Obstructive, occupational and environmental diseases
endocrine abnormalities affecting renal function, then review the more modern vascular theories.
Hypoxemia, hypercapnia, and renal-endocrine abnormalities Although renal-endocrine levels are elevated in COPD, interventions targeted at these mechanisms have failed. In a study of COPD patients with chronic hypoxemia, their elevated baseline serum aldosterone levels were reduced after the administration of an angiotensin-converting enzyme inhibitor, but sodium excretion was not improved, indicating that the sodium retention was not mediated by aldosterone [19]. Another study demonstrated substantial elevations of urinary dopamine output, plasma renin activity, and especially atrial natriuretic peptide during acute COPD exacerbations [20]. This and other studies demonstrated that oxygen therapy improved renal excretion of sodium, but had no effect on these renal hormonal levels [21,22]. The relative importance of hypoxemia versus hypercapnia has varied among studies and study populations. Early investigators observed that abnormal sodium excretion was very common among patients with chronic hypercapnea, but uncommon among those with only hypoxemia and no hypercapnea [21,23]. Sharkey et al. [24], in a study of 14 patients with acute exacerbations of COPD, found that renovascular resistance was increased in hypoxemic patients, but could be reversed with administration of oxygen. However, subsequent addition of just 1 l per minute of carbon dioxide again increased the renovascular resistance, suggesting that carbon dioxide might have the more potent effect. Another study examined the effects of longterm oxygen treatment (LTOT) in 19 patients with COPD who had normal baseline creatinine levels but nighttime hypoxemia [25]. At baseline, renal function, as measured by clearance of administered insulin and para-amino-hippurate, was reduced by 35 and 45%, respectively, while the filtration fraction (clearance of inulin/clearance of papa-aminohippurate) was 31% higher than normal. Lower baseline nighttime oxygen saturations correlated with greater improvements in postoxygen treatment filtration fraction (r ¼ 0.73, P < 0.05). Overall renal function did not change after 6 months of oxygen therapy, but sodium clearance did change and was affected by changes in carbon dioxide levels (PaCO2). In conclusion, renal function was reduced in COPD, and filtration fraction was improved by LTOT solely in patients with severe pretreatment hypoxemia. Sodium clearance was increased if improved oxygenation was not accompanied by increased PaCO2, suggesting as in the study by 190
www.co-pulmonarymedicine.com
Sharkey at al. [24] that PaCO2 retention is a key effect modifier in the relationship between COPD and renal function. In contrast, a third study examined the effects of oxygen therapy on the renal hemodynamics and renal function of 12 COPD patients who had borderline daytime hypoxemia (average PaO2 56 mmHg) [26]. Oxygenation improved the GFR, sodium excretion, and diuresis, but had no effect on renal plasma flow. Unlike the previous two studies, these changes occurred despite a mild increase in PCO2, suggesting that oxygen therapy caused renal improvement independently of hypercapnia. Another study of 25 stable COPD patients found quite different results [27]. As with other studies, hypercapnia and impaired lung function were clearly associated with edema, low diuresis, low GFR and RBF, and high renal vascular resistance. However, hypoxemia was not associated with renal function, and hypoxia had no significant effect on sodium or fluid retention. The discrepancies among these studies are likely to be in part attributable to the small and heterogeneous study populations, the different clinical situations (e.g., acute exacerbations of COPD versus clinically stable patients), and variations in study methods. Although the role of hypoxia is inconclusive in these COPD clinical studies, the role of hypoxia as an important biologic mechanism in end-stage renal failure is recognized [28]. Hypoxia of renal tubular cells leads to either apoptosis or differentiation of epithelial and mesenchymal cells into fibroblasts, which leads to tubulointerstital fibrosis, worsening diffusion of oxygen, and thus a vicious circle of worsening scarring. Many of the known renal-endocrine abnormalities associated with COPD, such as the elevation of angiotensin, reduce oxygen delivery by constriction of efferent arterioles while also reducing the efficient utilization of oxygen through oxidative stress. Oxygen tension within kidneys is normally relatively low (from 10 mmHg in the medulla to 30 mmHg in the cortex), making them susceptible to reduced oxygen delivery from either reduced blood flow, anemia, or low oxygen saturations. Relatively few clinical studies have examined chronic hypoxemia from lung disease or sleep apnea as independent risk factors for the loss of renal function [29], but several basic studies on kidney pathophysiology suggest a variety of possible oxygen-related causal mechanisms.
Chronic obstructive pulmonary disease and vascular injury In recent studies, attention has shifted from renalendocrine abnormalities to large and small vessel Volume 20 Number 2 March 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Renal and hepatobiliary dysfunction in COPD Mapel
injury. It is already established that RBF is reduced during acute exacerbations of COPD, thus it is reasonable to expect that patients with severe COPD have a reduced or absent renal functional reserve, which could be a factor in their edema formation. Sharkey et al. [30] investigated renal functional reserve, which is the normal increase in RBF after a protein load, in stable COPD patients. As a surrogate measure of RBF, the pulsatility index, an index of renovascular resistance, was measured noninvasively by Doppler ultrasonography at baseline and after a protein load of 250 g steak. In normal individuals, the pulsatility index fell after the protein load from 1.04 to 0.84 (P < 0.001), while there was no significant change in the COPD group (baseline pulsatility index ¼ 1.04, pulsatility index after protein load ¼ 1.08). In hypercapnic patients, the pulsatility index actually increased from 1.03 at baseline to 1.12 after the protein load (P ¼ 0.06), suggesting that this is one mechanism by which COPD patients with hypercapnea appear to have a higher risk of renal failure. Another study examined the renal functional reserve in stable patients with COPD, and found that reduced functional reserve was detectable in even mild cases, and correlated with the severity of airflow obstruction [31 ]. Furthermore, persons with higher serum TNF-a levels had worse renal functional reserve, suggesting a possible causal link between systemic inflammation from COPD and renal injury. Endothelins are proteins produced in vascular endothelium that constrict blood vessels. They work in balance with other mechanisms to regulate regional perfusion, but when they are overexpressed they contribute to systemic hypertension, and when overproduced in the lungs they cause pulmonary hypertension. Sofia et al. [32] examined pulmonary and renal endothelin clearance in nine patients during acute COPD exacerbations to see if endothelins contribute to the renal response to hypoxemia and hypercapnia. Although absolute serum levels of endothelins were not substantially different, the 24 h urinary excretion of endothelin was significantly higher in COPD patients as compared with controls, both during exacerbation as well as after recovery. The GFR was 69.4 in COPD patients during exacerbation and increased to 95.5 at recovery (P < 0.001). Corrected renal clearance of endothelin was significantly correlated to GFR values during the exacerbation (r ¼ 0.81, P < 0.05), but not after recovery. Changes in endothelins were also associated with changes in PaCO2 (r ¼ 0.83, P < 0.001) and PaO2 (r ¼ 0.73, P < 0.05). In conclusion, acute exacerbation of COPD causes an increase in renal endothelin production that is partially reversible, suggesting &&
that endothelins are mediators between COPD and renal function. Albuminuria reflects increased permeability of the glomerulus caused by microvascular damage. It is associated with arterial stiffness in patients with diabetes and hypertension, and in persons without chronic illness. The urinary albumin to creatinine ratio (UACR) is a measure of renal loss that is elevated in COPD and is negatively correlated with arterial blood PaO2 levels [33]. John et al. [34 ] examined the relationship between aortic pulse wave velocity (PWV) as a measure of arterial stiffness and UACR in 52 COPD patients and 34 controls. The UACR was greater in COPD patients, and directly related to airflow obstruction. The aortic PWV was greater in COPD, and related to the UACR in all individuals as well as COPD. In conclusion, arterial stiffness associated with COPD is related to albuminuria, suggesting that glomerular microvascular injury is another causal mechanism of kidney damage in COPD. &&
CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND HEPATIC DISEASE Passive liver congestion from cor pulmonale was long ago recognized as a complication of end-stage COPD, but since then there have been few analyses of COPD comorbidities that have included hepatobiliary diseases [16]. In their nationwide review of all hospital admissions for COPD in Switzerland, Baty et al. [2 ] reported a prevalence of alcoholic cirrhosis of the liver of 1.15% among COPD cases as compared with 0.45% of age-matched and sex-matched controls (P < 0.001), but did not report on any other liver disease subcategories (Table 2). They did find that COPD patients had a substantially higher risk of alcohol-related diagnoses than controls (harmful use of alcohol: 1.58 versus 0.39%; alcohol dependence syndrome: 5.26 versus 1.39%). Interestingly, among the three subtypes of COPD analyzed (emphysema, chronic bronchitis, and asthma), alcohol abuse was highest among those with chronic bronchitis. In their population-based cohort of COPD patients from Spain, Garcı´a-Olmos et al. [6 ] found a prevalence of chronic liver disease of 4.99% overall, which was substantially higher in men (5.72%) than women (2.67%). Chronic liver disease was among the 10 chronic illnesses that were significantly more prevalent than expected (standardized prevalence ratio 1.89; 95% CI: 1.37–2.42). In our case–control study of 2284 COPD patients, we found that COPD patients did not have increased diagnoses of liver disease, but they did
1070-5287 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&&
&
www.co-pulmonarymedicine.com
191
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Obstructive, occupational and environmental diseases Table 2. Chronic obstructive pulmonary disease and hepatobiliary disease: epidemiology and risk factors Reference
Study design
Baty [2 ]
Population-based cohort with 1 : 1 case–control matching for admissions
Mapel [3 ]
COPD cases (n)
Findings
160 317
COPD patients had a higher prevalence of alcoholic cirrhosis of the liver (1.15%) than age-matched and sexmatched controls (0.45%) (OR 2.6: 95% CI 2.4–2.7). Prevalences of harmful use of alcohol (1.58 versus 0.39%), alcohol dependence (5.26 versus 1.39%), and psychoactive substance abuse (3.17 versus 0.65%) were substantially higher among COPD patients. (P < 0.001 for all comparisons)
Population-based cohort with 1 : 3 case–control matching for all COPD cases
2284
COPD patients had more gallbladder disease (2.76 versus 1.63%) and pancreatic disease (1.40 versus 0.60%) than did controls, but prevalence of chronic liver disease was not different. Abnormal hepatic laboratory values > 2 ULN were significantly more common in COPD. COPD patients had 38% more fills for potentially hepatotoxic drugs. (P < 0.01 for all comparisons)
Garcı´a-Olmos [6 ]
Population-based cohort
3124
CRF was diagnosed in 6.3% of COPD patients (7.1% of men, 3.9% of women), which was 28% higher than expected in this population (standardized prevalence ratio 1.28; 95% CI: 0.96–1.59)
Lin [35]
Retrospective cohort with 1 : 2 case–control matching
1388
Mild liver disease was reported in 2.95% of cases and 1.59% of matched controls (OR 1.89, 95% CI: 1.23– 2.91). Mean annual cost for COPD and liver disease was $14 331, as compared with average COPD cost of $7603, and average liver disease cost of $6050
&&
&&
&
CI, confidence interval; COPD, chronic obstructive pulmonary disease; CRF, chronic renal failure; OR, odds ratio; ULN, upper limit of normal.
have more gallbladder disease (2.76 versus 1.63%; P < 0.001) and pancreatic disease (1.40 versus 0.60%, P < 0.001) [3 ]. COPD patients were more likely than their controls to have at least a transaminase test that was more than two times the upper limit of normal (alanine aminotransferase: 3.2 versus 1.8%; aspartate aminotransferase: 4.5 versus 2.7%; P < 0.01 for both). We also found that COPD patients were dispensed more potentially hepatotoxic prescription drugs during the 3-year study period (27.4 fills for COPD patients versus 19.9 for controls; P < 0.001). The prevalence of hepatic disease and the impact of hepatic illness on cost were examined as part of a retrospective case–control analysis of comorbid conditions among 1388 COPD patients in the Northeastern United States [35]. Patients were Medicaid beneficiaries and were thus limited to ages 40–64. The prevalence of mild liver disease was 2.95% as compared with 1.59% among the matched controls (OR 1.89; 95% CI 1.23–2.91). Adjusted mean annual cost per COPD patient in this cohort was $7603, as compared with $5732 for controls (2001 US dollars). For COPD patients who also had mild liver disease, the mean annual cost was $14 331, versus $8281 for control patients with mild liver disease, resulting in an incremental cost difference of $6050. This was the third highest incremental cost increase among all COPD comorbidities,
outpaced only by diabetes with complications and peptic ulcer disease.
&&
192
www.co-pulmonarymedicine.com
CONCLUSION COPD was the third leading cause of death worldwide in 2010, and the ninth leading cause of global years of life lost, according to the Global Burden of Disease Study [36 ]. Therefore, the burden of even less common COPD comorbidities such as kidney and liver disease on the healthcare system is still quite substantial. The mechanisms of renal disease in COPD are very complex and not well understood, in large part because of the heterogeneity among COPD patients. Nevertheless, appreciation of the importance of hypoxia and systemic inflammation in the pathophysiology of CRF is helping to elucidate some of the possible causal associations. The relationships between hepatobiliary disease and COPD are less well known, but population-based case–control studies have consistently found increased risk. &
Acknowledgements None. Conflicts of interest The author previously was awarded an investigatorinitiated grant from Pfizer Pharmaceuticals for an analysis of the epidemiology of renal and hepatobiliary diseases in COPD. Volume 20 Number 2 March 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Renal and hepatobiliary dysfunction in COPD Mapel
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Schneider KM, O’Donnell BE, Dean D. Prevalence of multiple chronic conditions in the United States’ Medicare population. Health Qual Life Outcomes 2009; 7:82. 2. Baty F, Putora PM, Isenring B, et al. Comorbidities and burden of COPD: a && population based case-control study. PLoS One 2013; 8:e63285. The largest and most comprehensive population-based analysis of comorbidities in COPD, based on all hospitalizations for COPD in Switzerland from 2002 through 2010. 3. Mapel DW, Marton JP. Prevalence of renal and hepatobiliary disease, labora&& tory abnormalities, and potentially toxic medication exposures among persons with COPD. Int J Chron Obstruct Pulm Dis 2013; 8:127–134. A population-based case–control analysis with the unique features of prevalence by specific ICD-9 category, laboratory data, and utilization of medication that may contribute to renal or hepatic injury. 4. Mapel DW, Hurley JS, Frost FJ, et al. Healthcare utilization in chronic obstructive pulmonary disease. A case-control study in a health maintenance organization. Arch Intern Med 2000; 160:2653–2658. 5. Nobili A, Marengoni A, Tettamanti M, et al. Association between clusters of diseases and polypharmacy in hospitalized elderly patients: results from the REPOSI study. Eur J Intern Med 2011; 22:597–602. 6. Garcı´a-Olmos L, Alberquilla A, Ayala V, et al. Comorbidity in patients with & chronic obstructive pulmonary disease in family practice: a cross sectional study. BMC Fam Pract 2013; 14:11. A comprehensive assessment of comorbidities based on 3124 COPD patients identified in a network of primary care offices based in Madrid, Spain. 7. Ekstrom MP, Jogreus C, Strom KE. Comorbidity and sex-related differences in & mortality in oxygen-dependent chronic obstructive pulmonary disease. PLoS One 2012; 7:e35806. Detailed prevalence of specific comorbidies by sex in a cohort with severe COPD. 8. Gjerde B, Bakke PS, Ueland T, et al. The prevalence of undiagnosed renal & failure in a cohort of COPD patients in western Norway. Respir Med 2012; 106:361–366. One of the few studies that includes a detailed analysis of risk factors. 9. Incalzi RA, Corsonello A, Pedone C, et al. Chronic renal failure: a neglected comorbidity of COPD. Chest 2010; 137:831–837. 10. Chandra D, Stamm JA, Palevsky PM, et al. The relationship between pul& monary emphysema and kidney function in smokers. Chest 2012; 142:655– 662. The only study to include CT scan data in a large research cohort. 11. Singanayagam A, Schembri S, Chalmers JD. Predictors of mortality in && hospitalized adults with acute exacerbation of chronic obstructive pulmonary disease. Ann Am Thorac Soc 2013; 10:81–89. A meta-analysis of 37 articles and 189 772 patients that includes details about specific comorbidities. 12. Terzano C, Conti V, Di Stefano F, et al. Comorbidity, hospitalization, and mortality in COPD: results from a longitudinal study. Lung 2010; 188:321– 329. 13. Kent BD, Eltayeb EE, Woodman A, et al. The impact of chronic obstructive & pulmonary disease and smoking on mortality and kidney transplantation in end-stage kidney disease. Am J Nephrol 2012; 36:287–295. Detailed examination of COPD among 769 984 dialysis patients in the United States. 14. van Gestel YR, Chonchol M, Hoeks SE, et al. Association between chronic obstructive pulmonary disease and chronic kidney disease in vascular surgery patients. Nephrol Dial Transplant 2009; 24:2763–2767. 15. Rodrigues AJ, Evora PR, Bassetto S, et al. Risk factors for acute renal failure after heart surgery. Rev Bras Cir Cardiovasc 2009; 24:441–446.
16. Platts MM, Hammond JD, Stuart-Harris CH. A study of cor pulmonale in patients with chronic bronchitis. Q J Med 1960; 29:559–574. 17. White RJ, Woodings DF. Impaired water handling in chronic obstructive airways disease. Br Med J 1971; 2:561–563. 18. Farber MO, Roberts LR, Weinberger MH, et al. Abnormalities of sodium and H2O handling in chronic obstructive lung disease. Arch Intern Med 1982; 142:1326–1330. 19. Stewart AG, Waterhouse JC, Billings CG, et al. Effects of angiotensin converting enzyme inhibition on sodium excretion in patients with hypoxaemic chronic obstructive pulmonary disease. Thorax 1994; 49:995–998. 20. Howes TQ, Deane CR, Levin GE, et al. The effects of oxygen and dopamine on renal and aortic blood flow in chronic obstructive pulmonary disease with hypoxemia and hypercapnia. Am J Respir Crit Care Med 1995; 151 (2 Pt 1): 378–383. 21. Palange P. Renal and hormonal abnormalities in chronic obstructive pulmonary disease (COPD). Thorax 1998; 53:989–991. 22. Skwarski KM, Morrison D, Barratt A, et al. Effects of hypoxia on renal hormonal balance in normal subjects and in patients with COPD. Respir Med 1998; 92:1331–1336. 23. Campbell EJ, Short DS. The cause of oedema in ‘corpulmonale’. Lancet 1960; 1:1184–1186. 24. Sharkey RA, Mulloy EM, O’Neill SJ. The acute effects of oxygen and carbon dioxide on renal vascular resistance in patients with an acute exacerbation of COPD. Chest 1999; 115:1588–1592. 25. Bratel T, Ljungman S, Runold M, Stenvinkel P. Renal function in hypoxaemic chronic obstructive pulmonary disease: effects of long-term oxygen treatment. Respir Med 2003; 97:308–316. 26. Lima MR, Burdmann EA, Cipullo JP. Oxygen therapy improves renal function in patients with chronic obstructive pulmonary disease. Ren Fail 2005; 27:373–379. 27. Hemlin M, Ljungman S, Carlson J, et al. The effects of hypoxia and hypercapnia on renal and heart function, haemodynamics and plasma hormone levels in stable COPD patients. Clinical Respir J 2007; 1:80–90. 28. Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol 2006; 17:17–25. 29. Ahmed SB, Ronksley PE, Hemmelgarn BR, et al. Nocturnal hypoxia and loss of kidney function. PLoS One 2011; 6:e19029. 30. Sharkey RA, Mulloy EM, Kilgallen IA, O’Neill SJ. Renal functional reserve in patients with severe chronic obstructive pulmonary disease. Thorax 1997; 52:411–415. 31. Chen CY, Hsu TW, Mao SJ, et al. Abnormal renal resistive index in patients && with mild-to-moderate chronic obstructive pulmonary disease. COPD 2013; 10:216–225. Demonstrates that renal functional reserve is correlated with airway obstruction and systemic inflammation. 32. Sofia M, Maniscalco M, Celentano L, et al. Abnormalities of renal endothelin during acute exacerbation in chronic obstructive pulmonary disease. Pulm Pharmacol Ther 2001; 14:321–327. 33. Casanova C, de Torres JP, Navarro J, et al. Microalbuminuria and hypoxemia in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010; 182:1004–1010. 34. John M, Hussain S, Prayle A, et al. Target renal damage: the microvascular && associations of increased aortic stiffness in patients with COPD. Respir Res 2013; 14:31. Correlations between aortic stiffness, microalbuminuria, and hypoxemia are described in COPD. 35. Lin PJ, Shaya FT, Scharf SM. Economic implications of comorbid conditions among Medicaid beneficiaries with COPD. Respir Med 2010; 104:697– 704. 36. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 & causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380:2095– 2128. Describes the global burden of COPD relative to other diseases and their changes over the last 20 years.
1070-5287 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-pulmonarymedicine.com
193
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Renal and hepatobiliary dysfunction in chronic obstructive pulmonary disease Douglas Mapel
Purpose of review This review examines the associations between chronic obstructive pulmonary disease (COPD) and renal and hepatobiliary diseases, with emphasis on the epidemiology and clinical outcomes, along with current information on pathophysiologic mechanisms and risk factors. Recent findings Glomerular filtration, sodium retention, and waste excretion are abnormal in COPD and sensitive to hypoxemia and hypercarbia, but variably responsive to oxygen administration and angiotensin-converting enzyme inhibition. Newer concepts about the role of hypoxia on the progression of chronic renal failure, and improved understanding about the relationships between COPD, decreased arterial compliance, and renal glomerular injury, are bringing new insights about potential causal mechanisms between COPD and kidney diseases. Other than the well known relationship between cor pulmonale and passive liver congestion, little was known about the relationships between COPD and liver diseases until recent population-based surveys demonstrated that COPD patients have substantially elevated risk for specific hepatobiliary system diseases. Summary Renal complications of COPD are common especially among patients with hypoxemia and hypercarbia. Renal-endocrine mechanisms, tissue hypoxia, and vascular rigidity have roles in the pathophysiology, but understanding of causal relationships is not precise. COPD patients have increased risk for hepatobiliary diseases and asymptomatic elevations of hepatic transaminases, which fortunately have relatively low prevalence. Keywords chronic obstructive pulmonary disease, epidemiology, hepatobiliary, renal
INTRODUCTION Comorbid conditions are a major concern in the management of chronic obstructive pulmonary disease (COPD) patients largely because they are so common. In an analysis of 179 544 COPD patients in the United States, 32.7% had one other major chronic illness, and 39.0% had two or more [1]. However, among the many chronic conditions associated with COPD, there are relatively few published data on the incidence and prevalence of renal and hepatic disease. The reasons for this are not clear, but one explanation is that patients with diagnosed renal or hepatic diseases are usually excluded from clinical trials, and those found to have abnormal elevations in renal function tests or hepatic transaminases during screening are usually excluded. Another possible explanation for the lack of data is that renal and hepatic diseases less commonly cause clinical problems than heart www.co-pulmonarymedicine.com
disease, lung cancer, or other serious COPD comorbidities. Nevertheless, renal and hepatic complications associated with COPD were recognized even before the paradigm of COPD was developed in the early 1960s. Long before the systemic inflammatory mechanisms of COPD were appreciated, the neuroendocrine effects of COPD on renal function and the impact of hypoxemia and hypercarbia on renal blood flow (RBF) were described. The purpose of Lovelace Clinic Foundation, Health Services Research Division, Albuquerque, New Mexico, USA Correspondence to Douglas Mapel, MD, MPH, FCCP, Medical Director, Lovelace Clinic Foundation, Health Services Research Division, 2309 Renard Place SE, Suite 103, Albuquerque, NM 87106-4264, USA. Tel: +1 505 938 9900; e-mail: [email protected] Curr Opin Pulm Med 2014, 20:186–193 DOI:10.1097/MCP.0000000000000024 Volume 20 Number 2 March 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Renal and hepatobiliary dysfunction in COPD Mapel
KEY POINTS COPD is associated with increased risk of both acute and chronic renal failure, which is confirmed in a variety of epidemiologic studies from several countries. COPD with hypoxemia and hypercarbia is associated with sodium retention and reduced glomerular filtration, and is responsive to oxygen therapy but not fully explained by normal renal-endocrine mechanisms. Hypoxic damage to renal tubules and interstitium, along with glomerular damage caused by arterial stiffness, are possible causal mechanisms in the relationship between COPD and renal disease. COPD patients have a moderately increased risk for chronic hepatobiliary diseases, and limited data suggest they also have increased risk factors including alcohol and drug abuse, and increased use of potentially hepatotoxic medications.
this review is to review the relationships between COPD and renal and hepatic diseases, particularly the epidemiologic evidence, pathophysiologic mechanisms, and the factors that affect clinical outcomes.
CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND RENAL DISEASE: EPIDEMIOLOGY Data about the incidence, prevalence, and risk factors for renal disease in COPD come from a range of study designs and populations (Table 1). In the largest population-based analysis of comorbidities in COPD available, Baty et al. [2 ] examined every hospitalization for COPD in Switzerland for calendar years 2002 through 2010, and compared the diagnosed comorbidities among 340 948 COPD admissions (representing 160 317 individual patients) matched by age and sex to 340 948 admissions among non-COPD patients. Comorbidities were classified using the International Classification of Diseases (ICD)-10 coding system. The prevalence of renal disease was significantly elevated in four different categories: acute renal failure (1.80 versus 0.89%), chronic kidney disease (CKD) (4.39 versus 2.13%), CKD – unspecified (4.64 versus 2.25%), and unspecified kidney failure (3.03 versus 1.67%). Although all were highly significant differences (P < 0.001), kidney diseases did not make the top 10 among all COPD comorbidities in terms of prevalence or odds ratio (OR) risk. We conducted a cross-sectional populationbased study of all COPD patients enrolled in one managed care system in the Southwest United States [3 ]. To estimate the increased risk of renal failure &&
&&
and undiagnosed renal insufficiency associated with COPD, we matched each COPD case to three patients without COPD by age and sex. We also examined case–control differences in the use of potentially nephrotoxic drugs. The 2284 cases had approximately twice the incidence of acute renal failure (1.4 versus 0.6%, P < 0.01), and three times the prevalence of diagnosed chronic renal failure (CRF) (2.9 versus 0.8%, P < 0.01), than did the controls. Elevations in renal function tests were also common: 27.1% of the COPD cases had at least one abnormal creatinine level during the study period as compared with 16.7% of controls. Over the 3-year study period, COPD patients averaged 17.6 prescription fills for potentially nephrotoxic agents as opposed to 13.6 fills for controls. However, we did not adjust for differences in other comorbidities such as cardiovascular disease, which we have demonstrated are much higher in this COPD population [4]. Polypharmacy has been identified as a very common problem in other populations of COPD patients with CRF [5]. In a population-based, cross-sectional analysis of comorbidities in a primary care cohort from Madrid, Spain, the prevalence of chronic diseases among 3124 COPD patients was compared with the expected prevalence in this population, adjusted for age and sex [6 ]. Over 90% of COPD patients in this cohort had at least one other chronic condition, most commonly hypertension (52%). CRF was diagnosed in 6.3% overall: 7.1% in men and 3.9% in women. This was a calculated overall prevalence 28% higher than expected, but did not quite reach statistical significance (standardized prevalence ratio 1.28; 95% CI: 0.96–1.59). The prevalence of CRF was also higher among men than women in a registry of 8712 COPD patients from Sweden who had been started on long-term oxygen therapy [7 ]. The prevalence of CRF among women was 1.5% compared with 2.6% in men, with an adjusted OR of 0.58 (P < 0.001). Other comorbidities were also found to have different prevalences by sex, with women having more hypertension, osteoporosis, rheumatoid arthritis, and mental disorders, and men having more arrhythmias, heart disease, and cancer. However, the differences in comorbidities did not explain the better survival among women with COPD in this cohort [hazard ratio 0.73 (95% CI: 0.68–0.77)]. Factors associated with undiagnosed renal failure, defined as a glomerular filtration rate (GFR) less than 60 by the Cockcroft Gault formula, were examined in a cohort of 433 patients in a longitudinal cohort study in Norway [8 ]. Patients who had known renal failure were excluded from this nonrandom survey. In this cohort, women had a higher
1070-5287 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
&
&
www.co-pulmonarymedicine.com
187
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Obstructive, occupational and environmental diseases Table 1. Chronic obstructive pulmonary disease and renal disease: epidemiology and risk factors Reference
Study design
Baty [2 ]
Population-based cohort with 1 : 1 case–control matching for admissions
Mapel [3 ]
Population-based cohort with 1 : 3 case–control matching for all COPD cases
&&
COPD cases (n) Findings 160 317
Based on all hospitalized COPD patients in Switzerland in calendar years 2002–2010. COPD patients had increased odds of acute renal failure (OR 2.00) and all three ICD-10 categories for CRF (OR 1.80–2.10). (P < 0.001 for all comparisons)
2284
COPD patients had twice the incidence of acute renal failure (1.4 versus 0.6%), and three times the prevalence of diagnosed CRF (2.9 versus 0.8%), than did controls. Abnormal renal laboratory values > 2 ULN occurred in 27.1% of COPD cases as compared with 16.7% of controls. COPD patients had 30% more fills for potentially nephrotoxic drugs. (P < 0.01 for all comparisons)
Garcı´a-Olmos [6 ] Population-based cohort
3124
CRF was diagnosed in 6.3% of COPD patients (7.1% of men, 3.9% of women), which was 28% higher than expected in this population (standardized prevalence ratio 1.28; 95% CI: 0.96–1.59)
Ekstro ¨ m [7 ]
Registry of COPD patients on long-term oxygen
8712
CRF occurred in of 0.58 (95% other illnesses diabetes, and
Gjerde [8 ]
Research cohort
433
Undiagnosed renal failure was higher in COPD (6.9%) than a similar comparison group (0.8%), and more common in women with COPD (9.6%) than men (5.1%). Factors associated with renal failure included advanced age, cachexia, use of inhaled steroids, and systemic inflammatory markers
Incalzi [9]
Research cohort
356
COPD had more CRF (22.2% versus 13.4%) and ‘concealed’ renal failure (normal creatinine with reduced GFR) (20.8 versus 10.0%) as compared with similar controls
Research cohort
508
GFR and creatinine level were correlated with the severity of emphysema found on chest CT, but not with the severity of airflow obstruction by spirometry. Hypertension was associated with reduced renal function
&&
&
&
&
Chandra [10 ] &
1.5% of women and 2.6% of men, for an adjusted OR CI: 0.42–0.79). Women also had less prevalence of associated with renal failure, including hypertension, cardiovascular disease
CI, confidence interval; COPD, chronic obstructive pulmonary disease; CRF, chronic renal failure; GFR, glomerular filtration rate; ICD, International Classification of Diseases; OR, odds ratio; ULN, upper limit of normal.
prevalence of reduced GFR (9.6%) than men (5.1%). The overall prevalence of undiagnosed renal failure among COPD patients (6.9%) was much higher than in a similar comparison group (0.8%). Other factors associated with renal disease included advanced age, cachexia, use of inhaled steroids, and serum inflammatory markers including tumor necrosis factor. In a similar study from Italy, 356 elderly outpatients with COPD had a detailed evaluation to examine the prevalence of CRF (abnormal creatinine and GFR) and ‘concealed’ renal failure (normal creatinine but reduced GFR), as compared with an agematched and sex-matched cohort [9]. Each COPD patient was confirmed by pulmonary function testing and underwent a comprehensive physical and laboratory analysis. The prevalence of overt and concealed CRF in patients with COPD was 22.2 and 20.8%, respectively, as compared with 13.4 and 10.0% of controls. In multivariate models, age, diabetes, hypoalbuminemia, and musculo-skeletal diseases were significant correlates of concealed 188
www.co-pulmonarymedicine.com
CRF, whereas age, increased BMI, and diabetes were significantly associated with overt CRF. The relationship between kidney function and the severity of emphysema was examined in a cohort of 508 COPD patients enrolled in a longitudinal clinical study [10 ]. Each patient had a comprehensive clinical evaluation including a computed tomography (CT) scan of the chest, from which the percentage of lung involvement with emphysema was estimated using both radiologists’ impressions and computerized analysis of regional attenuation. In both univariate and multivariate analyses, GFR and creatinine level were correlated with the severity of emphysema, but not with the severity of airflow obstruction by spirometry. The only other clinical factor associated with poor renal function in this COPD population was hypertension, but there was a relatively low prevalence of diabetes and other known renal disease risk factors in this cohort. The authors also examined the hypothesis that right heart failure was a contributing cause of renal insufficiency in COPD, but addition &
Volume 20 Number 2 March 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Renal and hepatobiliary dysfunction in COPD Mapel
of N-terminal pro-brain natriuretic peptide serum levels to the statistical models did not affect the relationship between emphysema and kidney disease.
RENAL DISEASE IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE: IMPACT ON CLINICAL OUTCOMES The relationship between COPD and renal disease and their impact on clinical outcomes can be examined from three perspectives: How does renal failure impact COPD prognosis? How does COPD impact prognosis among persons with chronic renal disease? How do both interact in the outcomes of patients having major procedures? Predictors of mortality among persons hospitalized with a COPD exacerbation were examined in a systematic literature review published by Singanayagam et al. [11 ]. A total of 37 articles, incorporating data from 189 772 study individuals, were included in the meta-analysis. Outcomes were stratified as short-term mortality (90 days or less) and long-term mortality (90 days to 2 years after initial presentation). Renal failure, along with 11 other prognostic factors (age, male sex, low BMI, cardiac failure, confusion, long-term oxygen therapy, lower limb edema, Global Initiative for Chronic Lung Disease stage 4, cor pulmonale, acidemia, and elevated troponin level), was significantly associated with increased short-term mortality. However, renal failure was not among the nine prognostic factors (age, low BMI, cardiac failure, diabetes mellitus, ischemic heart disease, malignancy, forced expiratory volume in 1 s, long-term oxygen therapy, and PaO2 on admission) that were significantly associated with long-term mortality. Renal failure doubled the risk of short-term mortality (OR 1.97; 95% CI: 1.31– 2.94) among the 100 206 persons in the analysis with comparable data, but the point estimate was highly variable across the included studies. Prognostic factors, including risk for hospitalization and mortality, among COPD patients were examined in a prospective study of 288 who were hospitalized for COPD exacerbations and then followed for up to 7 years [12]. Hypertension was the most common comorbidity (64.2%), followed by CRF (26.3%), diabetes mellitus (25.3%), and cardiac diseases (22.1%). However, among the chronic diseases, mortality risk was only related to the presence of cor pulmonale, ischemic heart disease, and lung cancer. Number and length of hospital admissions depended primarily on measures of the severity of lung disease and not on renal failure. Kent et al. [13 ] examined the impact of COPD on a cohort of 769 984 dialysis patients included in &&
&
the US Renal Data System registry between May 1995 and December 2004. The prevalence of diagnosed COPD was 7.5% overall, and increased from 6.7 to 8.1% during the time period. COPD was associated with advanced age, cardiovascular disease, cancer, malnutrition, poor functional status, and current cigarette smoking. Adjusted mortality was significantly increased among the COPD patients [relative risk (RR) ¼ 1.20; 95% CI: 1.18– 1.21], especially the current smokers (RR ¼ 1.28; 95% CI: 1.25–1.32). Persons with COPD were much less likely to be offered kidney transplantation. Renal disease and COPD both have strong associations with atherosclerosis, which led van Gestel et al. [14] to examine how COPD and renal disease affected outcomes among 3371 persons who had undergone peripheral vascular surgery (abdominal aortic repair, carotid endarterectomy, or lower limb arterial reconstruction). CKD was found in 27% and COPD in 39% of this cohort at the time of surgery. COPD was more prevalent in those with CKD (46%) than those without it (36%), and the prevalence of COPD increased with the reduction in GFR. However, there was not a linear association between the severity of airflow obstruction and the risk for CKD at baseline. In long-term follow up, moderate and severe COPD were associated with increased mortality among those with CKD in both univariate and multivariate analyses. Risk factors for acute postoperative renal failure were examined in a prospective case series of 769 patients who underwent cardiac surgery in one academic medical center in Brazil [15]. Seventy-eight patients (10% of cohort) developed renal failure postoperatively, 18 of whom required dialysis. The baseline prevalence of diagnosed COPD was only 4.3%, but COPD patients had four times higher risk of developing renal failure (adjusted OR 4.11; 95% CI: 1.63–10.4).
MECHANISMS OF RENAL MALFUNCTION AND INJURY IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE Problems with abnormal sodium excretion and water retention were noted among patients with chronic bronchitis over half a century ago, particularly if they had chronic hypoxemia or hypercapnia [16]. Initially, this was attributed to the consequences of cor pulmonale, which reduces RBF and GFR, increases aldosterone levels, and may also result in abnormal secretion of antidiuretic hormone [17,18]. However, subsequent research demonstrated that renal-endocrine abnormalities did not adequately explain renal malfunction in COPD. We first review the renal hypoxia, hypercapnia, and
1070-5287 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-pulmonarymedicine.com
189
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Obstructive, occupational and environmental diseases
endocrine abnormalities affecting renal function, then review the more modern vascular theories.
Hypoxemia, hypercapnia, and renal-endocrine abnormalities Although renal-endocrine levels are elevated in COPD, interventions targeted at these mechanisms have failed. In a study of COPD patients with chronic hypoxemia, their elevated baseline serum aldosterone levels were reduced after the administration of an angiotensin-converting enzyme inhibitor, but sodium excretion was not improved, indicating that the sodium retention was not mediated by aldosterone [19]. Another study demonstrated substantial elevations of urinary dopamine output, plasma renin activity, and especially atrial natriuretic peptide during acute COPD exacerbations [20]. This and other studies demonstrated that oxygen therapy improved renal excretion of sodium, but had no effect on these renal hormonal levels [21,22]. The relative importance of hypoxemia versus hypercapnia has varied among studies and study populations. Early investigators observed that abnormal sodium excretion was very common among patients with chronic hypercapnea, but uncommon among those with only hypoxemia and no hypercapnea [21,23]. Sharkey et al. [24], in a study of 14 patients with acute exacerbations of COPD, found that renovascular resistance was increased in hypoxemic patients, but could be reversed with administration of oxygen. However, subsequent addition of just 1 l per minute of carbon dioxide again increased the renovascular resistance, suggesting that carbon dioxide might have the more potent effect. Another study examined the effects of longterm oxygen treatment (LTOT) in 19 patients with COPD who had normal baseline creatinine levels but nighttime hypoxemia [25]. At baseline, renal function, as measured by clearance of administered insulin and para-amino-hippurate, was reduced by 35 and 45%, respectively, while the filtration fraction (clearance of inulin/clearance of papa-aminohippurate) was 31% higher than normal. Lower baseline nighttime oxygen saturations correlated with greater improvements in postoxygen treatment filtration fraction (r ¼ 0.73, P < 0.05). Overall renal function did not change after 6 months of oxygen therapy, but sodium clearance did change and was affected by changes in carbon dioxide levels (PaCO2). In conclusion, renal function was reduced in COPD, and filtration fraction was improved by LTOT solely in patients with severe pretreatment hypoxemia. Sodium clearance was increased if improved oxygenation was not accompanied by increased PaCO2, suggesting as in the study by 190
www.co-pulmonarymedicine.com
Sharkey at al. [24] that PaCO2 retention is a key effect modifier in the relationship between COPD and renal function. In contrast, a third study examined the effects of oxygen therapy on the renal hemodynamics and renal function of 12 COPD patients who had borderline daytime hypoxemia (average PaO2 56 mmHg) [26]. Oxygenation improved the GFR, sodium excretion, and diuresis, but had no effect on renal plasma flow. Unlike the previous two studies, these changes occurred despite a mild increase in PCO2, suggesting that oxygen therapy caused renal improvement independently of hypercapnia. Another study of 25 stable COPD patients found quite different results [27]. As with other studies, hypercapnia and impaired lung function were clearly associated with edema, low diuresis, low GFR and RBF, and high renal vascular resistance. However, hypoxemia was not associated with renal function, and hypoxia had no significant effect on sodium or fluid retention. The discrepancies among these studies are likely to be in part attributable to the small and heterogeneous study populations, the different clinical situations (e.g., acute exacerbations of COPD versus clinically stable patients), and variations in study methods. Although the role of hypoxia is inconclusive in these COPD clinical studies, the role of hypoxia as an important biologic mechanism in end-stage renal failure is recognized [28]. Hypoxia of renal tubular cells leads to either apoptosis or differentiation of epithelial and mesenchymal cells into fibroblasts, which leads to tubulointerstital fibrosis, worsening diffusion of oxygen, and thus a vicious circle of worsening scarring. Many of the known renal-endocrine abnormalities associated with COPD, such as the elevation of angiotensin, reduce oxygen delivery by constriction of efferent arterioles while also reducing the efficient utilization of oxygen through oxidative stress. Oxygen tension within kidneys is normally relatively low (from 10 mmHg in the medulla to 30 mmHg in the cortex), making them susceptible to reduced oxygen delivery from either reduced blood flow, anemia, or low oxygen saturations. Relatively few clinical studies have examined chronic hypoxemia from lung disease or sleep apnea as independent risk factors for the loss of renal function [29], but several basic studies on kidney pathophysiology suggest a variety of possible oxygen-related causal mechanisms.
Chronic obstructive pulmonary disease and vascular injury In recent studies, attention has shifted from renalendocrine abnormalities to large and small vessel Volume 20 Number 2 March 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Renal and hepatobiliary dysfunction in COPD Mapel
injury. It is already established that RBF is reduced during acute exacerbations of COPD, thus it is reasonable to expect that patients with severe COPD have a reduced or absent renal functional reserve, which could be a factor in their edema formation. Sharkey et al. [30] investigated renal functional reserve, which is the normal increase in RBF after a protein load, in stable COPD patients. As a surrogate measure of RBF, the pulsatility index, an index of renovascular resistance, was measured noninvasively by Doppler ultrasonography at baseline and after a protein load of 250 g steak. In normal individuals, the pulsatility index fell after the protein load from 1.04 to 0.84 (P < 0.001), while there was no significant change in the COPD group (baseline pulsatility index ¼ 1.04, pulsatility index after protein load ¼ 1.08). In hypercapnic patients, the pulsatility index actually increased from 1.03 at baseline to 1.12 after the protein load (P ¼ 0.06), suggesting that this is one mechanism by which COPD patients with hypercapnea appear to have a higher risk of renal failure. Another study examined the renal functional reserve in stable patients with COPD, and found that reduced functional reserve was detectable in even mild cases, and correlated with the severity of airflow obstruction [31 ]. Furthermore, persons with higher serum TNF-a levels had worse renal functional reserve, suggesting a possible causal link between systemic inflammation from COPD and renal injury. Endothelins are proteins produced in vascular endothelium that constrict blood vessels. They work in balance with other mechanisms to regulate regional perfusion, but when they are overexpressed they contribute to systemic hypertension, and when overproduced in the lungs they cause pulmonary hypertension. Sofia et al. [32] examined pulmonary and renal endothelin clearance in nine patients during acute COPD exacerbations to see if endothelins contribute to the renal response to hypoxemia and hypercapnia. Although absolute serum levels of endothelins were not substantially different, the 24 h urinary excretion of endothelin was significantly higher in COPD patients as compared with controls, both during exacerbation as well as after recovery. The GFR was 69.4 in COPD patients during exacerbation and increased to 95.5 at recovery (P < 0.001). Corrected renal clearance of endothelin was significantly correlated to GFR values during the exacerbation (r ¼ 0.81, P < 0.05), but not after recovery. Changes in endothelins were also associated with changes in PaCO2 (r ¼ 0.83, P < 0.001) and PaO2 (r ¼ 0.73, P < 0.05). In conclusion, acute exacerbation of COPD causes an increase in renal endothelin production that is partially reversible, suggesting &&
that endothelins are mediators between COPD and renal function. Albuminuria reflects increased permeability of the glomerulus caused by microvascular damage. It is associated with arterial stiffness in patients with diabetes and hypertension, and in persons without chronic illness. The urinary albumin to creatinine ratio (UACR) is a measure of renal loss that is elevated in COPD and is negatively correlated with arterial blood PaO2 levels [33]. John et al. [34 ] examined the relationship between aortic pulse wave velocity (PWV) as a measure of arterial stiffness and UACR in 52 COPD patients and 34 controls. The UACR was greater in COPD patients, and directly related to airflow obstruction. The aortic PWV was greater in COPD, and related to the UACR in all individuals as well as COPD. In conclusion, arterial stiffness associated with COPD is related to albuminuria, suggesting that glomerular microvascular injury is another causal mechanism of kidney damage in COPD. &&
CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND HEPATIC DISEASE Passive liver congestion from cor pulmonale was long ago recognized as a complication of end-stage COPD, but since then there have been few analyses of COPD comorbidities that have included hepatobiliary diseases [16]. In their nationwide review of all hospital admissions for COPD in Switzerland, Baty et al. [2 ] reported a prevalence of alcoholic cirrhosis of the liver of 1.15% among COPD cases as compared with 0.45% of age-matched and sex-matched controls (P < 0.001), but did not report on any other liver disease subcategories (Table 2). They did find that COPD patients had a substantially higher risk of alcohol-related diagnoses than controls (harmful use of alcohol: 1.58 versus 0.39%; alcohol dependence syndrome: 5.26 versus 1.39%). Interestingly, among the three subtypes of COPD analyzed (emphysema, chronic bronchitis, and asthma), alcohol abuse was highest among those with chronic bronchitis. In their population-based cohort of COPD patients from Spain, Garcı´a-Olmos et al. [6 ] found a prevalence of chronic liver disease of 4.99% overall, which was substantially higher in men (5.72%) than women (2.67%). Chronic liver disease was among the 10 chronic illnesses that were significantly more prevalent than expected (standardized prevalence ratio 1.89; 95% CI: 1.37–2.42). In our case–control study of 2284 COPD patients, we found that COPD patients did not have increased diagnoses of liver disease, but they did
1070-5287 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&&
&
www.co-pulmonarymedicine.com
191
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Obstructive, occupational and environmental diseases Table 2. Chronic obstructive pulmonary disease and hepatobiliary disease: epidemiology and risk factors Reference
Study design
Baty [2 ]
Population-based cohort with 1 : 1 case–control matching for admissions
Mapel [3 ]
COPD cases (n)
Findings
160 317
COPD patients had a higher prevalence of alcoholic cirrhosis of the liver (1.15%) than age-matched and sexmatched controls (0.45%) (OR 2.6: 95% CI 2.4–2.7). Prevalences of harmful use of alcohol (1.58 versus 0.39%), alcohol dependence (5.26 versus 1.39%), and psychoactive substance abuse (3.17 versus 0.65%) were substantially higher among COPD patients. (P < 0.001 for all comparisons)
Population-based cohort with 1 : 3 case–control matching for all COPD cases
2284
COPD patients had more gallbladder disease (2.76 versus 1.63%) and pancreatic disease (1.40 versus 0.60%) than did controls, but prevalence of chronic liver disease was not different. Abnormal hepatic laboratory values > 2 ULN were significantly more common in COPD. COPD patients had 38% more fills for potentially hepatotoxic drugs. (P < 0.01 for all comparisons)
Garcı´a-Olmos [6 ]
Population-based cohort
3124
CRF was diagnosed in 6.3% of COPD patients (7.1% of men, 3.9% of women), which was 28% higher than expected in this population (standardized prevalence ratio 1.28; 95% CI: 0.96–1.59)
Lin [35]
Retrospective cohort with 1 : 2 case–control matching
1388
Mild liver disease was reported in 2.95% of cases and 1.59% of matched controls (OR 1.89, 95% CI: 1.23– 2.91). Mean annual cost for COPD and liver disease was $14 331, as compared with average COPD cost of $7603, and average liver disease cost of $6050
&&
&&
&
CI, confidence interval; COPD, chronic obstructive pulmonary disease; CRF, chronic renal failure; OR, odds ratio; ULN, upper limit of normal.
have more gallbladder disease (2.76 versus 1.63%; P < 0.001) and pancreatic disease (1.40 versus 0.60%, P < 0.001) [3 ]. COPD patients were more likely than their controls to have at least a transaminase test that was more than two times the upper limit of normal (alanine aminotransferase: 3.2 versus 1.8%; aspartate aminotransferase: 4.5 versus 2.7%; P < 0.01 for both). We also found that COPD patients were dispensed more potentially hepatotoxic prescription drugs during the 3-year study period (27.4 fills for COPD patients versus 19.9 for controls; P < 0.001). The prevalence of hepatic disease and the impact of hepatic illness on cost were examined as part of a retrospective case–control analysis of comorbid conditions among 1388 COPD patients in the Northeastern United States [35]. Patients were Medicaid beneficiaries and were thus limited to ages 40–64. The prevalence of mild liver disease was 2.95% as compared with 1.59% among the matched controls (OR 1.89; 95% CI 1.23–2.91). Adjusted mean annual cost per COPD patient in this cohort was $7603, as compared with $5732 for controls (2001 US dollars). For COPD patients who also had mild liver disease, the mean annual cost was $14 331, versus $8281 for control patients with mild liver disease, resulting in an incremental cost difference of $6050. This was the third highest incremental cost increase among all COPD comorbidities,
outpaced only by diabetes with complications and peptic ulcer disease.
&&
192
www.co-pulmonarymedicine.com
CONCLUSION COPD was the third leading cause of death worldwide in 2010, and the ninth leading cause of global years of life lost, according to the Global Burden of Disease Study [36 ]. Therefore, the burden of even less common COPD comorbidities such as kidney and liver disease on the healthcare system is still quite substantial. The mechanisms of renal disease in COPD are very complex and not well understood, in large part because of the heterogeneity among COPD patients. Nevertheless, appreciation of the importance of hypoxia and systemic inflammation in the pathophysiology of CRF is helping to elucidate some of the possible causal associations. The relationships between hepatobiliary disease and COPD are less well known, but population-based case–control studies have consistently found increased risk. &
Acknowledgements None. Conflicts of interest The author previously was awarded an investigatorinitiated grant from Pfizer Pharmaceuticals for an analysis of the epidemiology of renal and hepatobiliary diseases in COPD. Volume 20 Number 2 March 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Renal and hepatobiliary dysfunction in COPD Mapel
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Schneider KM, O’Donnell BE, Dean D. Prevalence of multiple chronic conditions in the United States’ Medicare population. Health Qual Life Outcomes 2009; 7:82. 2. Baty F, Putora PM, Isenring B, et al. Comorbidities and burden of COPD: a && population based case-control study. PLoS One 2013; 8:e63285. The largest and most comprehensive population-based analysis of comorbidities in COPD, based on all hospitalizations for COPD in Switzerland from 2002 through 2010. 3. Mapel DW, Marton JP. Prevalence of renal and hepatobiliary disease, labora&& tory abnormalities, and potentially toxic medication exposures among persons with COPD. Int J Chron Obstruct Pulm Dis 2013; 8:127–134. A population-based case–control analysis with the unique features of prevalence by specific ICD-9 category, laboratory data, and utilization of medication that may contribute to renal or hepatic injury. 4. Mapel DW, Hurley JS, Frost FJ, et al. Healthcare utilization in chronic obstructive pulmonary disease. A case-control study in a health maintenance organization. Arch Intern Med 2000; 160:2653–2658. 5. Nobili A, Marengoni A, Tettamanti M, et al. Association between clusters of diseases and polypharmacy in hospitalized elderly patients: results from the REPOSI study. Eur J Intern Med 2011; 22:597–602. 6. Garcı´a-Olmos L, Alberquilla A, Ayala V, et al. Comorbidity in patients with & chronic obstructive pulmonary disease in family practice: a cross sectional study. BMC Fam Pract 2013; 14:11. A comprehensive assessment of comorbidities based on 3124 COPD patients identified in a network of primary care offices based in Madrid, Spain. 7. Ekstrom MP, Jogreus C, Strom KE. Comorbidity and sex-related differences in & mortality in oxygen-dependent chronic obstructive pulmonary disease. PLoS One 2012; 7:e35806. Detailed prevalence of specific comorbidies by sex in a cohort with severe COPD. 8. Gjerde B, Bakke PS, Ueland T, et al. The prevalence of undiagnosed renal & failure in a cohort of COPD patients in western Norway. Respir Med 2012; 106:361–366. One of the few studies that includes a detailed analysis of risk factors. 9. Incalzi RA, Corsonello A, Pedone C, et al. Chronic renal failure: a neglected comorbidity of COPD. Chest 2010; 137:831–837. 10. Chandra D, Stamm JA, Palevsky PM, et al. The relationship between pul& monary emphysema and kidney function in smokers. Chest 2012; 142:655– 662. The only study to include CT scan data in a large research cohort. 11. Singanayagam A, Schembri S, Chalmers JD. Predictors of mortality in && hospitalized adults with acute exacerbation of chronic obstructive pulmonary disease. Ann Am Thorac Soc 2013; 10:81–89. A meta-analysis of 37 articles and 189 772 patients that includes details about specific comorbidities. 12. Terzano C, Conti V, Di Stefano F, et al. Comorbidity, hospitalization, and mortality in COPD: results from a longitudinal study. Lung 2010; 188:321– 329. 13. Kent BD, Eltayeb EE, Woodman A, et al. The impact of chronic obstructive & pulmonary disease and smoking on mortality and kidney transplantation in end-stage kidney disease. Am J Nephrol 2012; 36:287–295. Detailed examination of COPD among 769 984 dialysis patients in the United States. 14. van Gestel YR, Chonchol M, Hoeks SE, et al. Association between chronic obstructive pulmonary disease and chronic kidney disease in vascular surgery patients. Nephrol Dial Transplant 2009; 24:2763–2767. 15. Rodrigues AJ, Evora PR, Bassetto S, et al. Risk factors for acute renal failure after heart surgery. Rev Bras Cir Cardiovasc 2009; 24:441–446.
16. Platts MM, Hammond JD, Stuart-Harris CH. A study of cor pulmonale in patients with chronic bronchitis. Q J Med 1960; 29:559–574. 17. White RJ, Woodings DF. Impaired water handling in chronic obstructive airways disease. Br Med J 1971; 2:561–563. 18. Farber MO, Roberts LR, Weinberger MH, et al. Abnormalities of sodium and H2O handling in chronic obstructive lung disease. Arch Intern Med 1982; 142:1326–1330. 19. Stewart AG, Waterhouse JC, Billings CG, et al. Effects of angiotensin converting enzyme inhibition on sodium excretion in patients with hypoxaemic chronic obstructive pulmonary disease. Thorax 1994; 49:995–998. 20. Howes TQ, Deane CR, Levin GE, et al. The effects of oxygen and dopamine on renal and aortic blood flow in chronic obstructive pulmonary disease with hypoxemia and hypercapnia. Am J Respir Crit Care Med 1995; 151 (2 Pt 1): 378–383. 21. Palange P. Renal and hormonal abnormalities in chronic obstructive pulmonary disease (COPD). Thorax 1998; 53:989–991. 22. Skwarski KM, Morrison D, Barratt A, et al. Effects of hypoxia on renal hormonal balance in normal subjects and in patients with COPD. Respir Med 1998; 92:1331–1336. 23. Campbell EJ, Short DS. The cause of oedema in ‘corpulmonale’. Lancet 1960; 1:1184–1186. 24. Sharkey RA, Mulloy EM, O’Neill SJ. The acute effects of oxygen and carbon dioxide on renal vascular resistance in patients with an acute exacerbation of COPD. Chest 1999; 115:1588–1592. 25. Bratel T, Ljungman S, Runold M, Stenvinkel P. Renal function in hypoxaemic chronic obstructive pulmonary disease: effects of long-term oxygen treatment. Respir Med 2003; 97:308–316. 26. Lima MR, Burdmann EA, Cipullo JP. Oxygen therapy improves renal function in patients with chronic obstructive pulmonary disease. Ren Fail 2005; 27:373–379. 27. Hemlin M, Ljungman S, Carlson J, et al. The effects of hypoxia and hypercapnia on renal and heart function, haemodynamics and plasma hormone levels in stable COPD patients. Clinical Respir J 2007; 1:80–90. 28. Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol 2006; 17:17–25. 29. Ahmed SB, Ronksley PE, Hemmelgarn BR, et al. Nocturnal hypoxia and loss of kidney function. PLoS One 2011; 6:e19029. 30. Sharkey RA, Mulloy EM, Kilgallen IA, O’Neill SJ. Renal functional reserve in patients with severe chronic obstructive pulmonary disease. Thorax 1997; 52:411–415. 31. Chen CY, Hsu TW, Mao SJ, et al. Abnormal renal resistive index in patients && with mild-to-moderate chronic obstructive pulmonary disease. COPD 2013; 10:216–225. Demonstrates that renal functional reserve is correlated with airway obstruction and systemic inflammation. 32. Sofia M, Maniscalco M, Celentano L, et al. Abnormalities of renal endothelin during acute exacerbation in chronic obstructive pulmonary disease. Pulm Pharmacol Ther 2001; 14:321–327. 33. Casanova C, de Torres JP, Navarro J, et al. Microalbuminuria and hypoxemia in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010; 182:1004–1010. 34. John M, Hussain S, Prayle A, et al. Target renal damage: the microvascular && associations of increased aortic stiffness in patients with COPD. Respir Res 2013; 14:31. Correlations between aortic stiffness, microalbuminuria, and hypoxemia are described in COPD. 35. Lin PJ, Shaya FT, Scharf SM. Economic implications of comorbid conditions among Medicaid beneficiaries with COPD. Respir Med 2010; 104:697– 704. 36. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 & causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380:2095– 2128. Describes the global burden of COPD relative to other diseases and their changes over the last 20 years.
1070-5287 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-pulmonarymedicine.com
193
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
