Malnutrition and inflammation are associated with impaired pulmonary function in patients with chronic kidney disease

Marcelo Mazza Nascimento1,2, Abdul Rashid Qureshi1, Peter Stenvinkel1, Roberto Pecoits-Filho1,3, Olof Heimbürger1, Tommy Cederholm4, Bengt Lindholm1 and Peter Bárány1

1 Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden, 2 Faculdade Evangélica de Medicina do Paraná, Curitiba, Brazil, 3 Pontificia Universidade Católica do Paraná, Curitiba, Brazil and 4 Department of Geriatric Medicine, Centre for Inflammation and Hematological Research, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden

Correspondence and offprint requests to: Peter Bárány, MD, PhD, Division of Renal Medicine K-56, Karolinska Institutet, Karolinska University Hospital, Huddinge, S-141 86 Stockholm, Sweden. Email: peter. barany{at}klinvet.ki.se



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Inflammation and malnutrition are common findings in patients with chronic kidney disease (CKD). We hypothesized that in inflamed and malnourished patients, respiratory and peripheral muscle dysfunction may have significant consequences on pulmonary function. The aim of this study was to investigate possible associations between pulmonary function and inflammation and malnutrition in patients with CKD.

Methods. We studied 109 patients (63% males; 53±12 years) at the initiation of dialysis treatment (GFR 7.5±2.5 ml/min). Pulmonary function tests [forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and peak expiratory flow (PEF)] were performed and the percentages of predicted values were calculated (%FEV1, %FVC and %PEF). Systemic inflammation, assessed by high-sensitivity C-reactive protein (hsCRP) and nutritional status assessed by subjective global assessment (SGA), lean body mass (LBM) (estimated with dual energy X-ray absorptiometry) and hand-grip strength (HGS), were evaluated at the same time.

Results. Significant negative correlations were found between hsCRP and the percent predicted values for all pulmonary function tests [%FEV1 (Rho = –0.45), %FVC (Rho = –0.43) and %PEF (Rho = –0.38)], respectively. Malnourished patients defined as SGA ≥2 had lower %FEV1 (64±19 vs 82±23%; P<0.001) and %FVC (67±18 vs 83±21%; P<0.001) than well nourished patients. Significant correlations were observed between HGS and %FVC (Rho = 0.38; P <0.001), %FEV1 (Rho = 0.37; P<0.001) and %PEF (Rho = 0.22; P<0.05) and between LBM and %PEF (Rho = 0.20; P<0.05). Multivariate Cox analysis showed that cardiovascular disease and low %FVC were associated with poor survival.

Conclusions. Impaired pulmonary function is associated with malnutrition and inflammation, and predicts mortality in CKD patients. This may reflect an impact of malnutrition and inflammation on respiratory muscle performance, leading to pulmonary dysfunction, which could influence the clinical outcome.

Keywords: chronic kidney disease; inflammation; malnutrition; pulmonary function



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Approximately 30–50% of patients with chronic kidney disease (CKD) have serological evidence of an activated inflammatory response with elevated serum levels of C-reactive protein (CRP). In CKD patients the acute phase response may be influenced by a number of factors such as age, race, residual renal function and gender [1]. As part of the acute phase response, monocytes from CKD patients are activated and produce high levels of pro-inflammatory cytokines such as interleukin-6 and tumour necrosis factor {alpha}.

These cytokines may affect nutrition by inducing proteolysis in muscle, increasing energy expenditure, and inhibiting appetite, thereby leading to malnutrition [2]. It is well documented that protein–energy malnutrition and wasting are common phenomena that may be important risk factors for morbidity and mortality among CKD patients [3]. Recent reports have focused on the association between nutritional status and clinical outcome and between nutritional status and inflammation, providing evidence that inflammation may cause or contribute to increased mortality in this population [4].

Reduced respiratory and forearm muscle strength have been described as functional correlates to muscle wasting [5] in patients with chronic obstructive pulmonary disease (COPD). Respiratory and peripheral muscle dysfunction have significant consequences for malnourished COPD patients and both may be independent predictors of survival, in addition to the degree of airflow obstruction measured by the forced expiratory volume in 1 s (FEV1).

The aim of the present study was to determine if pulmonary dysfunction, as assessed by spirometry, is associated with malnutrition and inflammation in CKD stage 5 patients at initiation of renal replacement treatment. For this purpose, spirometric parameters were evaluated and analysed together with markers of nutritional status and inflammation. Furthermore, we tested whether spirometric values can predict clinical outcome.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients and study design
A total of 109 CKD stage 5 patients (68 males and 41 females), participating in an ongoing prospective study described previously [3,6], were investigated at the initiation of renal replacement therapy (RRT). The investigations were in most cases performed before starting RRT; however, 39 patients had just started RRT (median 9, range 1–56 days of treatment). The exclusion criteria were age > 70 years, unwillingness to participate in the study, acute renal failure and clinically overt infectious complications. The causes of renal failure included the following: diabetic nephropathy (n = 37), chronic glomerulonephritis (n = 20), unknown causes (n = 15) and other causes (n = 37). Thirty-three patients had a history of cardiovascular disease (CVD) (ischaemic heart disease, cerebrovascular disease or peripheral vascular disease), 59 were non-smokers, whereas 37 patients were ex-smokers, and 13 were current smokers. The mean residual renal function was 7.5±2.5 ml/min (assessed by the mean of urea and creatinine clearance). The patients were followed prospectively until the patient died or had a renal transplant. Informed consent was obtained from each patient and the Ethics Committee of the Karolinska Intitutet at Huddinge University Hospital approved the study.

Biochemical analysis
After an overnight fast, venous blood samples were taken, and if not analysed immediately, plasma samples were stored at –70°C. Inflammatory activity was assessed by determinations of high-sensitivity CRP (hsCRP) by nephelometric immunoassay with a detection limit of 0.1 mg/l. Serum albumin (S-Alb) (bromcresol purple method), haemoglobin, serum creatinine, urinary creatinine and urea were determined in the Department of Clinical Chemistry, Huddinge University Hospital, by routine methods.

Nutritional evaluation
Subjective global assessment (SGA) (n = 103), dual energy X-ray absorptiometry (DXA scan) (n = 79), hand-grip strength (HGS) (n = 98) and body mass index (BMI) (n = 109) were performed to evaluate nutritional status in this cohort of patients. According to the SGA score, patients were classified as well nourished (SGA = 1), or as having mild (SGA = 2), moderate (SGA = 3) or severe (SGA = 4) malnutrition [6]. For simplicity, the patients were combined in two groups; malnourished (SGA ≥ 2) and well nourished (SGA = 1). DXA scan was carried out, usually performed after blood sampling, using the DPX-L machine (Lunar Corp, Madison, WI, USA) and data were evaluated using Lunar software version 3.4. With this technique, bone mineral, fat and lean body mass (LBM) distribution is directly estimated without making assumptions of the two compartment model [6]. HGS was evaluated in both the dominant and non-dominant arm using the Harpenden dynamometer (British Indicators Ltd). HGS were repeated three times, and the greatest value was recorded. Because many patients had an arteriovenous fistula in the non-dominant arm, data from the dominant arm were used in the analysis. The individual values for HGS were normalized by converting them to percent of controls, when included in the statistical analyses. BMI was calculated as body weight in kg/height (m)2.

Pulmonary function
Pulse oximetry (SpO2) was performed with a Datex-Engstrom Finger Sensor (Datex-Engstrom Division, Instrumentarium Division, Finland) measuring red and infrared light absorption. The accuracy is ±2% in the SpO2 interval 80–100%. The spirometric assessments: forced vital capacity (FVC), forced expiratory volume in the first second (FEV1) and peak expiratory flow (PEF) were obtained using a Spirolab (Medical International Research, Rome, Italy) with flow accuracy ±5% and volume accuracy ±3%. Predicted normal values were calculated using the formulas by Crapo et al (%FEV1, %FVC). At least three reproducible tests were carried out for each measurement and the best was recorded.

Statistical analysis
Data are presented as mean±SD or median and range. A P-value < 0.05 was considered statistically significant. Continuous variables of two groups were compared using the Mann–Whitney U-test. The analysis of categorical variables was made by the analysis of contingency tables. We used the Spearman rank test for correlations between variables. We used the multivariate Cox proportional hazard model to assess the factors that had influence on the clinical outcome. We followed the patients for 36 months and we censored the patients for renal transplantation (n = 6). There were 17 deaths during the follow-up period of 36 months. The cut-off point for hsCRP (7.0 mg/l) as predictor of death was chosen according to the receiver operating characteristics (ROC) curve, reaching a sensitivity and specificity of 61 and 65%, respectively. The area under the ROC curve was 0.61, with a standard error 0.05, and a 95% confidence interval of 0.47–0.75.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Clinical data
Nutritional and spirometric parameters are given in Table 1. The mean age of the patients was 53±12 years (range 22–70 years), and BMI was 25±4 kg/m2 (range 16–37 kg/m2). Malnutrition was present in 31 patients (30%). As expected, LBM and HGS were significantly higher in males than in females, but there were no significant gender differences regarding SGA, hsCRP and predicted values of spirometric tests (%FEV1, %FVC, PEF and %FEV1/%FVC). Twenty patients had a %FEV1/%FVC ratio below 70%, indicating obstructive pulmonary disease and 15 patients with a normal %FEV1/%FVC ratio and low %FVC had restrictive disease.


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Table 1. Clinical, laboratory and spirometric data in 109 CKD patients

 
Comparison between patients according to SGA, inflammation and CVD
The patients were divided in two groups according to nutritional status assessed by SGA (Table 2). The malnourished patients were significantly older, had lower values of S-Alb and HGS, and higher levels of hsCRP and had lower predicted levels of %FEV1 and %FVC than the well nourished patients. No significant differences between the two groups were found with regard to the %FEV1/FVC and the percentage of predicted PEF.


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Table 2. Clinical and spirometric characteristics according to SGA

 
In Table 3 the patients are divided according to hsCRP levels. The patients with hsCRP >7 mg/l (cut-off value of hsCRP as a predictor of death according to the ROC curve, see Subjects and Methods) were significantly older and had a higher prevalence of malnutrition, lower HGS, lower S-Alb levels and lower predicted values of %FEV1, %FVC, %FEV1/FVC and PEF, whereas gender distribution, HGS and LBM were similar between the two groups.


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Table 3. Clinical and spirometric characteristics according to hsCRP <7 and ≥7 mg/l

 
The patients with CVD were significantly older and had lower S-Alb, higher levels of hsCRP, lower %FEV1 and %FVC than patients without CVD. Gender, history of smoking, SGA, HGS, PEF and LBM did not differ between the two groups.

Correlations between nutritional, inflammatory and spirometric parameters
There were several significant correlations between nutritional, inflammatory and spirometric (%FEV1, %FVC and PEF) parameters. HGS was significantly correlated with age (Rho = –0.40), S-Alb (Rho = 0.30), FEV1 (Rho = 0.49), FVC (Rho = 0.50) and hsCRP (Rho = 0.32). Moreover, there were significant correlations between hsCRP and age (Rho = 0.45), S-Alb (Rho = –0.36), %FEV1 (Rho = –0.45), %FVC (Rho = –0.43) and PEF (Rho = –0.38).

Cox proportional hazard analysis of survival
Univariate analyses showed that malnutrition (SGA, S-Alb, HGS), inflammation (hsCRP), comorbidities (CVD, DM), age and spirometric parameters (%FEV1, %FVC) all predicted survival. The multivariate Cox model was used to identify independent significant predictors of survival (Table 4). Apart from age and gender, %FVC, CVD and hsCRP were included in the model as these parameters were the strongest survival predictors of the spirometric, comorbidity and inflammation/nutritional parameters, respectively. CVD and %FVC were significant independent predictors of mortality, whereas hsCRP, age and gender were not independent predictors in this analysis.


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Table 4. Cox proportional hazards multivariate analysis of factors associated with clinical outcome

 


   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In the present study we found significant associations between respiratory function, nutritional status and inflammation in CKD patients. To the best of our knowledge, the effect of respiratory function on clinical outcome has previously not been reported in CKD patients. Patients with inflammation were significantly older and had a higher prevalence of malnutrition, lower S-Alb levels and lower predicted values of %FEV1, %FVC, %FEV1/%FVC and PEF. Earlier observations in CKD patients of strong associations between inflammation, malnutrition and CVD, factors that may all influence the clinical outcome, are here extended to include respiratory function as a predictor of outcome. It is likely that muscle wasting in patients with malnutrition and inflammation also affects respiratory muscles, which is an important determinant of the dynamic ventilatory capacity.

The findings in the present study indicate that muscle mass as assessed by LBM correlates positively with lung function in CKD patients. Forced inspiration requires muscular contraction to overcome air pressure on the surface area of the chest and an association between respiratory muscle strength, maximal inspiratory pressure and FVC has been reported among older individuals [9]. In non-renal elderly patients, Santana et al. [10] showed that the amount of muscle mass, correlates positively with lung function. Indeed, these authors demonstrated positive correlations between fat free mass and FVC and FEV1, respectively. This finding was also observed in non-uraemic elderly malnourished patients, by the demonstration of an association between reduced HGS and impaired pulmonary function, as expressed by PEF [11]. As reported previously, HGS is markedly influenced by the nutritional status in CKD patients, and it correlates with other nutritional parameters such as LBM and SGA [12]. In the present study, HGS showed a strong correlation not only with other nutritional markers such as age, LBM, SGA and S-Alb, but also with respiratory parameters %FEV1, %FVC and PEF. These findings suggest that skeletal muscle dysfunction in malnourished CKD patients can also result in impaired respiratory muscle function.

The systemic inflammatory response and accumulation of pro-inflammatory cytokines may contribute to protein calorie malnutrition by a variety of mechanisms in CKD patients. Pro-inflammatory cytokines may influence nutritional status through inhibition of appetite, alteration of gastrointestinal function, alteration of the carbohydrate metabolism and insulin resistance, and by increasing the rate of muscle and protein breakdown [13]. Further evidence for the importance of inflammation in these interactions, is provided by the tendency of an improvement in PEF, after nutritional intervention in non-renal elderly patients, without on-going inflammatory activity, while patients with such activity did not respond to nutrition therapy [14]. It has been suggested that at least two types of malnutrition may be present in CKD patients. Type 1 malnutrition is associated with anorexia due to the uraemic syndrome per se, whereas Type 2 malnutrition is mainly ‘cytokine-driven’ and characterized by more marked hypoalbuminaemia, higher resting energy expenditure, markedly increased oxidative stress, and increased protein catabolism [15]. An inflammatory response usually occurs in Type 2 malnutrition, as evidenced by higher levels of CRP and pro-inflammatory cytokines. In the present study, 49% of patients with high hsCRP had malnutrition.

In the general population, reduced pulmonary function, as assessed by FEV1 and FVC, is associated with an increased incidence of CVD and increased mortality. This association has been established in both smokers and non-smokers [16]. In the present study, the mortality was increased in CKD patients with low (< 80% of predictive value) values of FVC, suggesting a predictive role of pulmonary function also in CKD patients. In the present study, current or previous smoking did not seem to influence pulmonary function or clinical outcome, but the patient numbers may be too small for exploring these effects. Another respiratory abnormality that possibly could exert a detrimental effect and increase the mortality in dialysis patients is nocturnal hypoxaemia, which has been associated with a nocturnal rise in arterial pressure and left ventricular hypertrophy [17]. There were 21 patients in the present study who had pulse oxymetry levels < 97% but their spirometric results were not different from the patients with higher oxymetry levels. However, it is possible that the patients with low ventilatory capacity are more inclined to hypoxaemic episodes during sleep and HD sessions.

The cause of the relationship between spirometric parameters and CVD mortality is to a large extent unknown, but recent findings confirm that pulmonary function covariates with inflammation and the acute phase response, which are strongly associated with an increased cardiovascular risk [18]. In the present study, we found that the patients with CVD were significantly older and had lower %FEV1, %FVC, S-Alb and higher levels of hsCRP. In addition, loss of LBM, poor respiratory muscle function and reduced peripheral skeletal muscle function are independent predictors of mortality in COPD patients [16].

Some shortcomings of the current study should be considered. First, the number of patients in the present study is limited and the statistical power of multivariate analyses, such as the Cox proportional hazard model, are therefore low. Larger studies are needed to clarify the possible role of other potential cardiovascular risk factors. Secondly, although there were no significant differences in pulmonary tests between the patients who had just started RRT and those investigated before RRT start, the results might be affected by the dialysis procedure. We find this unlikely since a previous report in peritoneal dialysis patients did not demonstrate that the filling of dialysate into the peritoneal cavity had any effect on respiratory function [19]. Furthermore, Herrero et al. [20] did not observe differences in FEV1 and FVC in pre-dialysis and HD patients.

In conclusion, the present study demonstrates close relationships between lung function and inflammation and malnutrition in CKD patients. Malnutrition and inflammation are associated with loss of muscle mass and this may also affect respiratory muscles, potentially contributing to the impaired pulmonary function in CKD patients. The observed associations between malnutrition, inflammation and respiratory function and between these factors and clinical outcome require further investigations of their causes and consequences, and possible associations with hypoxaemia.

Conflict of interest statement. None declared.



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 29. 6.03
Accepted in revised form: 4. 2.04





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