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1 From the Nutrition Program (SU and MAK), Division of Nephrology (CMA, SAD, and LC), and the Department of Preventive Medicine (SA), Federal University of São Paulo, São Paulo, Brazil
2 Supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and the Oswaldo Ramos Foundation. 3 Address reprint requests to L Cuppari, Rua Pedro de Toledo, 282, 04039-000, São Paulo, SP, Brazil. E-mail: lilian{at}dis.epm.br.
ABSTRACT
Background: Inflammation, a clinical condition observed in patients with chronic kidney disease (CKD), may be related to increased resting energy expenditure (REE).
Objectives: The main objective was to investigate the relation between inflammation and REE in patients with CKD who are not undergoing dialysis. We also aimed to analyze whether a decrease in C-reactive protein (CRP) would result in a reduction in REE.
Design: This study enrolled 132 patients with CKD who were not undergoing dialysis, who had creatinine clearance from 5 to 65 mL · min1 · 1.73 m2, and who were 53.6 ± 16 y old; 82 (62.1%) were men. Twenty-nine patients had clinical signs of infection. REE was measured by using indirect calorimetry, and inflammation was evaluated by using high-sensitivity CRP measurement. Patients were divided according to tertiles of CRP with the following intertertile ranges: first tertile, CRP 0.14 mg/dL (n = 43); second tertile, CRP 0.150.59 mg/dL (n = 46); and third tertile, CRP 0.60 mg/dL (n = 43). REE was measured before and after treatment in 10 patients who had inflammation or infection.
Results: After adjustment for age, sex, and lean body mass, the REE of the third (1395 kcal/d; P = 0.02) and second (1355 kcal/d; P = 0.04) tertiles was significantly higher than that of the first tertile (1286 kcal/d). In the multiple linear regression analysis (n = 132), the independent determinants of REE were lean body mass, CRP, and age (R2 = 0.55). After treatment of infection in a subgroup of 10 patients, it was observed that a significant reduction in CRP concentration was accompanied by a significant reduction of 174 ± 165 kcal that accounted for 13% of the initial REE.
Conclusion: This study showed that inflammation is associated with increased REE in patients with CKD.
Key Words: Chronic kidney disease resting energy expenditure inflammation C-reactive protein protein-energy malnutrition
INTRODUCTION
Protein-energy malnutrition is common among patients with chronic kidney disease (CKD) (13). The cause of malnutrition in CKD is complex and includes many factors, such as poor food intake (4, 5), enhanced protein catabolism (6), hormonal disturbances (6), and increased resting energy expenditure (REE) (7). More recently, inflammation has also been pointed to as an important factor in a worsening of the nutritional status. Clinical and subclinical infections are frequent complications that lead to an inflammatory response in patients with CKD (8).
The primary inflammatory response is mediated by proinflammatory cytokines such as tumor necrosis factor , interleukin 6, and interferon-. Interleukin 6 is the main mediator of acute-phase protein synthesis, including serum amyloid A, fibrinogen, and C-reactive protein (CRP), which are considered markers of systemic inflammation (9). Cross-sectional studies have shown that 2550% of patients who are undergoing hemodialysis and peritoneal dialysis or not undergoing dialysis present serologic evidence of an activated inflammatory response with elevated serum concentrations of CRP (1012). The importance of these findings in patients with CKD rests on the association between inflammation and the occurrence of malnutrition (13, 14). Although the exact mechanisms involved in this association are still not clear, it has been shown that the inflammatory cytokines lead to increased protein catabolism (15, 16), enhanced lipolysis (17), suppression of appetite (5), and increased REE (18). In other diseases associated with an inflammatory condition, an association between elevated REE and inflammatory markers has been reported (1921). Our group recently investigated this issue in patients with CKD with subclinical inflammation who were not undergoing dialysis. We showed that REE was significantly higher in those patients with CRP concentrations >0.5 mg/dL (22). This suggests that inflammation, even when subclinical, might increase REE. Considering the harmful effects of a sustained elevation of REE on the nutritional status of these patients, we aimed to extend our investigations into the relation among infections, inflammation, and REE. For this purpose, we analyzed the REE of a large group of patients with CKD and with a wide range of serum CRP concentrations. In addition, we also studied the REE in a subgroup of infected patients after treatment or cure of the infectious disease and the subsequent decrease in CRP.
SUBJECTS AND METHODS
Subjects
This study enrolled 132 nondialysis patients with CKD from the renal outpatient clinic of the Federal University of São PauloOswaldo Ramos Foundation (São Paulo, SP, Brazil). Exclusion criteria included the following: age < 18 y, altered thyroid function, diabetes mellitus, pregnancy, and the use of corticosteroid or immunosuppressive agents. Of the entire group, 29 patients had clinical signs or laboratory data (or both) that were indicative of infection, such as urinary infection, diagnosed by positive urine culture (n = 10); gastric ulcer, diagnosed by the presence of Helicobacter pylori (n = 1); and renal tuberculosis, diagnosed by presence of the Koch bacillus in the urine sample (n = 1). Other infections were varicose ulcer (n = 2), erysipelas (n = 1), herpes zoster (n = 1), pneumonia (n = 1), pharyngitis (n = 1), and influenza (n = 11), which were diagnosed by clinical symptoms. Of the 132 enrolled patients, 118 (89.4%) were taking diuretics or antihypertensive medications or both, and 43 (32.6%) were taking ß-blockers. Vitamin supplementation (folic acid, B vitamins, or both) was taken by 57 patients (43.2%). A diet containing 3035 kcal · kg1 · d1 and 0.60.8 g protein · kg1 · d1 had been prescribed for 111 patients (84%).
For the second part of the study, we selected the patients with the following conditions: presence of clinical sign of infection plus CRP concentrations >0.5 mg/dL and a decrease in CRP concentration after treatment of the infection condition. Of 29 patients with infections, only 10 met these criteria. This subgroup of 10 patients had infections such as influenza (n = 4), urinary infection (n = 2), pharyngitis (n = 1), pneumonia (n = 1), renal tuberculosis (n = 1), and varicose ulcer (n = 1). All patients were treated, and antibiotics were administered when appropriate.
Written informed consent was obtained from each subject. The study was approved by the Human Investigation Review Committee of the Federal University of São Paulo.
Study protocol
All patients participated in an initial interview to verify the inclusion criteria and to provide informed consent. The patients were also instructed to collect urine over a 24-h period. On the same day of REE measurement, the subjects underwent fasting blood tests (including CRP) and body-composition and nutritional assessments. In the subgroup of 10 patients, these measurements were repeated after treatment of infection. The mean interval between the 2 measurements was 102 ± 69 d.
Biochemical data
Blood samples were drawn after an overnight fast of 12 h. Serum creatinine, urea, and glucose were measured by using a standard autoanalyzer. We measured bicarbonate (normal range: 2327 mmol/L) with an automated potentiometer, thyroid-stimulating hormone (normal range: 0.34.0 mIU/L) with immunofluorometric assays, and albumin (normal range: 3.44.8 g/dL) by using the green bromocresol technique. Intact parathyroid hormone (normal range: 1065 pg/mL) and high-sensitivity assay for CRP (inflammatory state: >0.5 mg/dL) were ascertained by using immunochemiluminescence. In all but the 10 patients whose CRP had been measured before and after treatment of infection, only a single measurement of CRP was taken. Assay analytic sensitivity for CRP was 0.02 mg/dL, and the interassay variability was 10%, 6%, 5%, and 7% for very low, low, medium, and high values, respectively. Intraassay variation was 5%, 5.3%, 4.2%, and 6.4% for very low, low, medium, and high CRP values, respectively. Glomerular filtration rate was evaluated by using standard creatinine clearance (CrCl) corrected for body surface area (1.73 m2).
Resting energy expenditure
REE was measured by indirect calorimetry with the use of an open-circuit, ventilated, computerized metabolic system (Vmax series 29n; SensorMedics Corp, Yorba Linda, CA). Initially, the flow sensor was calibrated with a syringe piston to adjust it for measuring high and low inspiratory and expiratory flow. Before each REE measurement, the oxygen and carbon dioxide sensors were calibrated by using mixed reference gases of known composition. All subjects had been instructed to maintain their regular medication, to refrain from any unusual physical activity in the 24-h period before the test, and to maintain their usual sleep schedule the night before REE measurement. They were admitted to the clinic at 0800 after a 12-h overnight fast. After 30 min of rest in a recumbent position, subjects breathed through a clear plastic canopy, placed over their heads, for 30 min in a quiet, dimly lit, thermally neutral room. They were instructed to avoid hyperventilation, fidgeting, or falling asleep during the test. Oxygen consumption (
RESULTS
The main characteristics of the 132 patients are shown in Table 1. Overall, patients did not show signs of malnutrition, because the mean standard percentages of midarm muscle circumference and the standard percentages of triceps skinfold thickness were within the normal range. In addition, BMI was indicative of overweight. The protein intake evaluated by normalized PNA was higher than the amount of protein prescribed, and serum albumin was within the normal range. Creatinine clearance varied from 5 to 65 mL/min, which is indicative of stages 25 of CKD (28). The main causes of CKD were hypertensive nephrosclerosis (n = 39; 30%), chronic glomerulonephritis (n = 15; 11%), and polycystic kidney disease (n = 17; 13%). Nineteen patients (15%) had CKD due to other causes, and the cause of CKD was not identified in 42 patients (31%). All patients had normal thyroid function. Higher CRP concentrations (defined as CRP > 0.5 mg/dL) were found in 53 patients (40.2%). Serum urea was 87.9 ± 40.8 mg/dL, serum bicarbonate was 22.6 ± 5.2 mmol/L, parathyroid hormone was 146 pg/mL (geometric
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TABLE 1. Characteristics of the patients1
The independent determinants of REE were lean body mass, CRP, and age (R2 = 0.55), as shown in Table 2 (n = 132). The main characteristics of the patients in each tertile of CRP are presented in Table 3. Except for BMI, standard percentage of triceps skinfold thickness, and REE, no differences were found between the CRP tertiles. After adjustment of REE for age, sex, and lean body mass, the REEs of the third (1395 kcal/d; P = 0.02) and second (1355 kcal/d; P = 0.04) tertiles were significantly higher than the REE of the first tertile (1286 kcal/d).
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TABLE 2. Multiple linear regression analysis with resting energy expenditure (REE) as a dependent variable1
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TABLE 3. Characteristics of the patients for each tertile of C-reactive protein (CRP)1
The subgroup of patients evaluated before and after treatment of infection were 5 women and 5 men with a mean age of 62 ± 18 y. As can be seen in Table 4, lean body mass, body fat, BMI, and CrCl did not change significantly after the treatment. In addition, a significant reduction in CRP concentration was accompanied by a significant reduction of 174 ± 165 kcal that accounted for 13.0% of the initial REE. This reduction was observed in 8 of the 10 patients studied.
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TABLE 4. Body composition, resting energy expenditure (REE), and laboratory indicators before and after treatment of infection1
DISCUSSION
The results of this study show that inflammation was associated with increased REE in patients with CKD who were not undergoing dialysis. In fact, REE was significantly higher in the highest CRP tertile even after adjustment for sex, age, and lean body mass. Moreover, in the multiple regression analysis, besides lean body mass and age, CRP was an independent determinant of REE. More important, in a subgroup of patients analyzed before and after treatment of infection, a decrease in CRP concentration was accompanied by a significant reduction in REE. Association between inflammatory markers and increased REE also was observed in other diseases, such as AIDS with opportunistic infections (20), rheumatoid arthritis (21), sepsis (18), and pancreatic cancer (19). Similar results in patients with CKD with a low degree of inflammation were observed recently by our group (22).
The mechanisms involved with the high REE observed in the present study cannot be fully identified. However, if one considers the metabolic disorders of the inflammatory response, such as fever (29), elevated
The importance of our findings relates to the deleterious effects of a sustained elevated REE. Besides its negative effect on nutritional status, increased REE has been associated with a high rate of mortality in patients who receive dialysis. In a group of 251 patients receiving continuous ambulatory peritoneal dialysis, it was found that those with higher REE had a rate of mortality higher than that in patients with lower REE (34). In addition, our findings highlight the importance of treating infection, because it might lead to an elevation of REE and thereby become another factor that contributes to aggravating the nutritional condition.
In conclusion, our findings showed that inflammation was associated with increased REE and that the reduction of CRP, subsequent to the treatment of subjacent infection, was accompanied by a significant decrease in REE. Further prospective studies focusing on treatment of chronic inflammation in patients with CKD could contribute to a better understanding of the effects of inflammation on both REE and malnutrition.
ACKNOWLEDGMENTS
We thank Fernando Antonio Basile Colugnati for his contribution in the statistical analysis.
SU and CMA were responsible for the data collection, interpretation of the results, and writing of the manuscript. SAD and MAK contributed to the interpretation of the results. SA contributed to the statistical analysis of the results. LC contributed to the conception and design of the study and to the writing of the manuscript. None of the authors had a personal or financial conflict of interest.
REFERENCES