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American Journal of Clinical Nutrition, Vol. 82, No. 2, 342-349, August 2005
© 2005 American Society for Clinical Nutrition

ORIGINAL RESEARCH COMMUNICATION

Inflammation contributes to low plasma amino acid concentrations in patients with chronic kidney disease1,2,3

Mohammed E Suliman, A Rashid Qureshi, Peter Stenvinkel, Roberto Pecoits-Filho, Peter Bárány, Olof Heimbürger, Björn Anderstam, Ernesto Rodríguez Ayala, José C Divino Filho, Anders Alvestrand and Bengt Lindholm

1 From the Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden

2 Supported by grants from the Baxter Healthcare Corporation, the Baxter Extramural Grant Program, the Swedish Medical Association, and the Karolinska Institute.

3 Reprints not available. Address correspondence to B Lindholm, the Divisions of Baxter Novum and Renal Medicine, Department of Clinical Science, Karolinska University Hospital Huddinge, K-56, S-141 86 Stockholm, Sweden. E-mail: bengt.lindholm{at}klinvet.ki.se.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Inflammation and malnutrition are common in chronic kidney disease (CKD) patients, and plasma concentrations of free amino acids (AAs) in these patients are often abnormal. Malnutrition contributes to alterations in AA concentrations.

Objective: The objective was to study the effects of inflammation on plasma AA concentrations.

Design: Concentrations of plasma AAs, serum albumin, and several inflammatory markers were analyzed in 200 fasting, nondiabetic CKD patients who were close to the start of renal replacement therapy. The nutritional status of these patients was assessed by a subjective global assessment.

Results: The patients with inflammation [C-reactive protein (CRP) concentrations >10 mg/L] or malnutrition had lower AA concentrations than did the patients with no inflammation or malnutrition. The presence of both inflammation and malnutrition was associated with more marked reductions in AA concentrations than was malnutrition alone. Significant inverse correlations were observed between the plasma concentrations of most of the essential and nonessential AAs and inflammatory markers, whereas serum albumin concentrations were positively correlated with several AA concentrations. A stepwise multivariate regression analysis showed that serum CRP concentrations were independently associated with low concentrations of the sums of both nonessential AAs and all AAs. An analysis of all-cause mortality with a Kaplan-Meier test showed that the patients with higher AA concentrations had significantly better survival than did the patients with lower AA concentrations.

Conclusions: Plasma AA concentrations are low in CKD patients with inflammation and are inversely correlated with concentrations of inflammatory markers. Although inflammation and malnutrition are closely related, CRP concentrations were independently associated with low concentrations of the sums of both nonessential AAs and all AAs, which suggests an independent role of inflammation as a cause of low plasma AA concentrations in CKD patients.

Key Words: Amino acids • cardiovascular disease • chronic kidney disease • C-reactive protein • inflammation • malnutrition • mortality


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Chronic kidney disease (CKD) is characterized by an exceptionally high mortality rate, primarily from cardiovascular disease (CVD). Chronic inflammation is a common feature in CKD patients and is associated with atherosclerotic CVD through various pathogenetic mechanisms (1). Moreover, the prevalence of protein-energy malnutrition in CKD patients is high, and inflammation is more prevalent in malnourished patients than in those with normal nutritional status (2, 3). A syndrome consisting of malnutrition, inflammation, and atherosclerosis is present in a large proportion of CKD patients and is associated with increased mortality (4).

Patients with CKD generally have an abnormal plasma amino acid (AA) pattern, ie, high plasma concentrations of several nonessential AAs (NEAAs) and low concentrations of most essential AAs (EAAs) (5–11). However, the mechanisms behind these abnormalities are not fully understood. Some of the changes are ascribed to derangements in AA metabolism, either because of deficient excretory and metabolic functions of the diseased kidneys or because of uremia per se. Inadequate nutritional intake and malnutrition may also contribute to plasma AA abnormalities. To some extent, the abnormal pattern of AAs seen in CKD patients resembles that seen in protein malnutrition, but the abnormal AA patterns are also observed in CKD patients with normal nutritional status (11). Because the biochemical changes that occur during inflammation exert a demand on AA metabolism (12), we hypothesized that the systemic inflammatory response seen in a large proportion of CKD patients may contribute to AA pattern disturbances.

The systemic inflammatory response stimulates protein catabolism (13, 14), and the release of AAs from muscle protein provides a substrate for the synthesis of acute phase proteins and proteins of the immune system (15), which could result in a general reduction in plasma AA concentrations. Because proinflammatory cytokines can cause anorexia and increased protein catabolism, they represent an important cause of protein wasting in CKD patients (16). Furthermore, proinflammatory cytokines activate inflammatory cells to produce reactive oxygen species, which may enhance AA oxidation. CKD patients often have signs of increased oxidative stress, which can also alter AA and protein concentrations in these patients.

In the present study, we hypothesized that inflammation, as evidenced by increased concentrations of C-reactive protein (CRP) and proinflammatory cytokines such as interleukin 6, is an important cause of plasma AA changes in CKD patients. For this purpose, concentrations of AAs and inflammatory markers from the plasma of fasting subjects were measured in a post hoc analysis of the baseline data of an ongoing prospective study in CKD patients who were starting dialysis treatment at baseline (2). To our knowledge, this was the first study to investigate a possible relation between plasma AA concentrations and inflammatory markers in CKD patients. Moreover, we studied the effects of both nutritional status and CVD on plasma AA concentrations. Furthermore, because the relation between AA concentrations and mortality has not been studied in CKD patients, the patients were followed from the start of dialysis therapy over a 5-y period to assess the effects of basal AA concentrations on all-cause mortality.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
The patients in the present study were included in a prospective cohort study of atherosclerosis and lipid metabolism in patients who were beginning dialysis replacement therapy at the Renal Clinic of the Karolinska University Hospital Huddinge, Stockholm, Sweden (2). In the present study, post hoc analyses of 200 CKD patients (120 men) with a median age of 53 y (range: 22–70 y) and a median glomerular filtration rate (GFR) of 7 mL/min (range: 1–16 mL/min) were conducted. The mean (±SD) body mass index (in kg/m2) was 25 ± 4. Exclusion criteria were age >70 y, liver dysfunction, diabetes mellitus, clinical signs of intercurrent infection, and unwillingness to participate in the study. Fifty-four (27%) patients had a clinical history or signs of cerebrovascular, cardiovascular, or peripheral vascular disease at the start of the study and were grouped as having clinical CVD (CVDclin). Of the 54 patients, 15 had a history of cerebrovascular disease (stroke), 31 had a history of CVD (acute myocardial infarction, angina pectoris, or coronary artery bypass surgery), 16 had a history of peripheral ischemic vascular disease, and 2 had a history of an aortic aneurysm. One hundred forty-three patients were studied before starting dialysis treatment (median time to start: 20 d), and 57 patients were studied just after starting dialysis treatment (median time from start: 8 d; see Results). Most patients were taking antihypertensive medications as well as other drugs that are commonly used by patients with CKD, such as phosphate and potassium binders, diuretics, and vitamin B, C, and D supplements. The protocol was approved by the Ethics Committee of Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden, and informed consent was obtained from each patient.

A population-based, randomly selected group of 39 control subjects (28 men) with a median age of 68 y (range: 38–80 y) was used for comparative analyses of AA concentrations. The control subjects were investigated with a protocol similar to that used for the patient group. The random selection of subjects in the Stockholm region was performed by Statistics Sweden (SCB). No other exclusion criteria, other than an unwillingness to participate in the study, was applied in the selection of the control group.

Blood sampling and laboratory analyses
After the patients fasted overnight, venous blood samples were taken and placed in appropriate tubes for the separation of plasma and serum, which were then stored at –70°C until analyzed. Plasma AA concentrations were measured with the use of reversed-phase HPLC and fluorometric detection, as described elsewhere (17). The routine procedures used in the Clinical Chemistry Laboratory at Huddinge University Hospital were used to measure serum concentrations of albumin (bromcresol purple), CRP (turbidimetry), fibrinogen, and creatinine and the urinary excretion of creatinine and urea. The detection limit of CRP was 10 mg/L, and all values <10 mg/L were treated as 9 mg/L in the statistical evaluation. High-sensitivity CRP was measured in 39 control subjects by nephelometry. The serum concentrations of tumor necrosis factor {alpha} and interleukin 6 were measured with a photometric enzyme-linked immunosorbent assay obtained from Boehringer Mannheim (Mannheim, Germany). Plasma neopterin concentrations were measured with a radioimmunoassay kit (Behring Diagnostic, Rueil-Malmaison, France). The concentrations of both the soluble intracellular adhesion molecule 1 and the soluble vascular cell adhesion molecule 1 were measured (n = 63 patients) with a commercially available enzyme-linked immunosorbent assay kit (R&D Systems Europe Ltd, Abingdon, United Kingdom). A specific radioimmunoassay kit was used to analyze plasma insulin concentrations (Pharmacia, Uppsala, Sweden).

Assessment of nutritional status and protein intake in the patients
A subjective global assessment (SGA) was used to evaluate the overall protein-energy nutritional status of the patients. The SGA included 6 subjective assessments: 3 were based on the patient’s history of weight loss, incidence of anorexia, and incidence of vomiting, and 3 were based on the physician’s grading of muscle wasting, presence of edema, and loss of subcutaneous fat. Each patient was given a score based on those assessments that reflected their nutritional status as follows: 1 = normal nutritional status, 2 = mild malnutrition, 3 = moderate malnutrition, and 4 = severe malnutrition. The patients with an ordinal SGA score of 2, 3, or 4 were grouped together as malnourished. Protein intake was estimated from the protein equivalent of nitrogen appearance (PNA), which was calculated from urea kinetic modeling by using the rate of urea excretion in a 24-h urine collection. Urine was collected from all of the patients before the start of dialysis therapy. PNA was normalized (nPNA) to actual body weight (ABW) and to standard body weight (SBW) with calculations based on the patient’s height, sex, age, and frame size with the use of National Health and Nutrition Examination Survey tables (18).

Outcome ascertainment
Survival was assessed from the day of examination, with a mean follow-up period of 16.7 mo (range: 0.5–60 mo). The patients were censored at death, when they received a kidney transplant, or when they completed the 5-y follow-up period; all patients participating in the present study were followed up. Within the follow-up period, 40 (20%) patients died and 80 (40%) patients received kidney transplants.

Statistical analyses
Values were expressed as medians (ranges) or means (±SDs), as appropriate. A P value < 0.05 was considered statistically significant. Comparisons between 2 groups were assessed for continuous variables with a Student’s unpaired t test; a Mann-Whitney U test was used when the distribution was skewed. Between-group comparisons were assessed for nominal variables with a chi-square test. Spearman’s rank correlation ({rho}) was used to assess the correlations between 2 variables. The difference between 4 groups was analyzed with the Kruskal-Wallis analysis of variance (ANOVA). To measure the degree of association between variables, a Wilks lambda 2-factor ANOVA was used. The model included a test for the effect of order. A generalized linear model was used to identify possible interactions between factors, and a post hoc test was used if there was a significant interaction. A stepwise multivariate regression analysis was used to assess the predictors for the sum of EAA concentrations, the sum of NEAA concentrations, and the sum of all AA concentrations. A survival analysis was made with the Kaplan-Meier test. All analyses were performed with the use of statistical software SAS version 9.1 (SAS Inc, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The clinical and biochemical characteristics of the control subjects and the patients studied are shown in Table 1Go. Fifty-seven patients in the present study had received dialysis therapy for a median of 8 d before the start of the study. However, CRP, AA, serum albumin, and serum creatinine concentrations and the prevalence of inflammation, malnutrition, and diabetes mellitus did not differ significantly between the 57 patients who had already started dialysis and the rest of the patients in the study (data not shown); therefore, all patients were analyzed as one group.


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  		TABLE 1 Characteristics of the control subjects, chronic kidney disease (CKD) patients, and 2 CKD patient subgroups1

 
The patients were divided into 2 groups on the basis of inflammatory status (2): patients with CRP concentrations <10 mg/L were classified as having no inflammation (n = 128), and patients with CRP concentrations ≥10 mg/L were classified as having inflammation (n = 72; Table 1Go). The patients with a concentration of CRP ≥10 mg/L were older and had a higher prevalence of both malnutrition (46% compared with 20%; P < 0.001) and CVDclin (38% compared with 21%; P < 0.05) than did the patients with a CRP concentration <10 mg/L; however, sex, body mass index, and GFR were not significantly different between the 2 patient groups. As expected, the serum concentrations of albumin and inflammatory markers differed between the 2 groups. The nPNA was significantly lower in patients with inflammation than in patients with no inflammation when nPNA was normalized to SBW; however, no significant differences were seen between the 2 patient groups when nPNA was normalized to ABW (Table 1Go). Serum insulin concentrations were significantly higher in the patients with inflammation than in the patients with no inflammation (Table 1Go) and were lower in malnourished than in nourished patients [11.5 (3.7–33.4) and 15.3 (3.6–50.3) µIU, respectively; P < 0.01].

The plasma concentrations of 7 NEAAs from fasting subjects were significantly higher in the CKD patients than in the control subjects, whereas the plasma concentrations of 5 EAAs and glutamine were significantly lower (Table 2Go). The other AA concentrations were not significantly different between the patients and the control subjects.


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  		TABLE 2 Comparison between plasma amino acid (AA) concentrations in healthy control subjects and chronic kidney disease (CKD) patients1

 
Compared with the 128 patients without inflammation, the 72 patients with inflammation had significantly lower concentrations of 7 NEAAs but not of glutamic acid, taurine, or ornithine. Of the EAAs, the plasma concentrations of histidine, threonine, lysine, methionine, and tryptophan were also significantly lower in the patients with inflammation than in the patients without inflammation.

Moreover, serum CRP concentrations were negatively correlated with plasma concentrations of asparagine, serine, glycine, citrulline, arginine, alanine, histidine, threonine, lysine, methionine, and tryptophan and were also negatively correlated with the sum of NEAA concentrations, the sum of EAA concentrations, and the sum of all AA concentrations [{rho} range: –0.16 (P < 0.05) to –0.40 (P < 0.0001)].

Interleukin 6 concentrations (n = 169) were negatively correlated with plasma concentrations of asparagine, serine, glycine, citrulline, alanine, histidine, tyrosine, and tryptophan and with the sum of NEAA concentrations and the sum of all AA concentrations [{rho} range: –0.15 (P < 0.05) to –0.28 (P < 0.01)]. Serum concentrations of tumor necrosis factor {alpha} (n = 151) showed negative correlations with citrulline, arginine, alanine, histidine, threonine, tryptophan, valine, isoleucine, and leucine concentrations and with the sum of branched-chain AA (BCAA) concentrations, the sum of EAA concentrations, and the sum of all AA concentrations [{rho} range: –0.16 (P < 0.05) to –0.25 (P < 0.01)].

Serum fibrinogen concentrations (n = 150) were also negatively correlated with the concentrations of asparagine, serine, glutamine, glycine, citrulline, arginine, alanine, histidine, threonine, lysine, and methionine and with the sum of NEAA concentrations, the sum of EAA concentrations, and the sum of all AA concentrations [{rho} range: –0.16 (P < 0.05) to –0.38 (P < 0.0001)].

Furthermore, serum neopterin concentrations (n = 115) were negatively correlated with concentrations of asparagine, citrulline, arginine, threonine, lysine, tryptophan, and valine and with the sum of NEAA concentrations and the sum of all AA concentrations [{rho} range: –0.19 (P < 0.05) to –0.27 (P < 0.01)]. Serum soluble intracellular adhesion molecule 1 and soluble vascular cell adhesion molecule 1 concentrations were negatively correlated with the concentrations of arginine, ornithine, tryptophan, valine, and isoleucine [{rho} range: –0.27 (P < 0.05) to –0.35 (P < 0.01)], whereas the inverse correlations with threonine ({rho} = –0.25, P = 0.06), histidine ({rho} = –0.24, P = 0.06), and phenylalanine ({rho} = –0.24, P = 0.06) were not statistically significant.

Serum albumin concentrations were positively correlated with the concentration of most AAs, including asparagine, glycine, citrulline, arginine, alanine, ornithine, histidine, threonine, tyrosine, lysine, methionine, tryptophan, phenylalanine, and valine and with the sum of NEAA concentrations, the sum of EAA concentrations, and the sum of all AA concentrations [{rho} range: 0.16 (P < 0.05) to 0.35 (P < 0.0001)]. However, we unexpectedly found that nPNA was not correlated with AA concentrations.

Twenty-nine percent of the patients were found to be malnourished when nutritional status was assessed by SGA (n = 196; data were not available for 4 patients; Table 1Go). Thirty-two of the malnourished patients (56%) had inflammation, whereas 38 (27%) of the patients with normal nutritional status had inflammation. The plasma concentrations of all EAAs (except tyrosine), a few NEAAs, and NEAA/EAA were significantly lower in the malnourished patients than in the patients with normal nutritional status (data not shown). In addition, nPNA was significantly lower in the malnourished patients than in the patients with normal nutritional status when nPNA was normalized to SBW (0.63 ± 16 compared with 0.71 ± 16 g · kg SBW–1 · d–1, P < 0.01), whereas nPNA was similar between the malnourished and nourished patients when it was normalized to ABW (0.72 ± 18 compared with 0.72 ± 15 g · kg ABW–1 · d–1).

The patients who underwent SGA (Table 3Go; n = 196) were divided into 4 groups on the basis of the presence of inflammation or malnutrition: group 1 (n = 101) included patients who had neither inflammation nor malnutrition, group 2 (n = 25) included patients who had only malnutrition, group 3 (n = 38) included patients who had only inflammation, and group 4 (n = 32) included patients who had both inflammation and malnutrition. Using a one-factor ANOVA, we found that the plasma concentrations of asparagine, serine, glutamine, glycine, citrulline, arginine, alanine, histidine, threonine, lysine, methionine, valine, and isoleucine and the sum of NEAA concentrations, the sum of BCAA concentrations, the sum of EAA concentrations, and the sum of all AA concentrations were significantly different between the 4 patient groups; patients in group 4 had the lowest AA concentrations. A further analysis by 2-factor ANOVA (Table 3Go) showed that several AAs were associated with inflammation as well as with malnutrition. However, none of the AAs showed significant malnutrition x inflammation interactions.


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  		TABLE 3 Plasma amino acid (AA) concentrations in chronic kidney disease (CKD) patients with neither inflammation nor malnutrition (group 1), with only malnutrition (group 2), with only inflammation (group 3), or with both inflammation and malnutrition (group 4)1

 
When the CKD patients were divided into 2 groups on the basis of the presence of CVDclin (Table 4Go), the plasma concentrations of glutamic acid, aspartic acid, alanine, histidine, threonine, methionine, and tryptophan and the sum of NEAA concentrations, the sum of EAA concentrations, and the sum of all AA concentrations were significantly lower in the patients with CVDclin than in the patients with no CVDclin.


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  		TABLE 4 Plasma amino acid (AA) concentrations in the chronic kidney disease patients with and without clinical cardiovascular disease (CVD)1

 
A stepwise multivariate regression analysis was used to determine the factors that were associated with plasma AA concentrations (Table 5Go) with the use of a model that included age, sex, GFR, SGA, and plasma insulin, serum albumin, and CRP concentrations. In 3 models that included the same variables, the sum of NEAA concentrations was independently associated with both sex and the concentrations of serum albumin and CRP; the sum of EAA concentrations was independently associated with sex, concentrations of serum albumin, and SGA; and the sum of all AA concentrations was independently associated with sex, GFR, and concentrations of serum albumin and CRP.


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  		TABLE 5 Stepwise multivariate regression analysis of predictors of plasma amino acid (AA) concentrations in chronic kidney disease patients1

 
We assessed the association between all-cause mortality and total AA concentrations using Kaplan-Meier survival curves based on the median concentration of AAs (2440 µmol/L). We noted a significant increase in all-cause mortality in patients with low concentrations of AAs (log-rank: 4.2; P = 0.04; Figure 1Go).



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  		FIGURE 1. The survival rate of patients with chronic kidney disease over a 5-y follow-up with regard to all-cause mortality and in relation to the median plasma concentration (2440 µmol/L) of total amino acids (AAs) at the start of renal replacement therapy. The Kaplan-Meier survival curves show that the patients with high AA concentrations had better survival rates than did the patients with low AA concentrations. Log-rank = 4.2, P < 0.05.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
To the best of our knowledge, this is the first study to show that plasma AA concentrations in fasting subjects are lower in CKD patients with inflammation than in CKD patients with no inflammation. The concentrations of most plasma AAs correlated inversely with the concentrations of several inflammatory markers, and a high CRP concentration was independently associated with low plasma AA concentrations. Moreover, as expected, plasma AA concentrations, particularly the EAAs, were lower in malnourished than in nourished patients and were even lower in patients with both inflammation and malnutrition. Finally, CKD patients with CVD and CKD patients who died had lower plasma AA concentrations than did CKD patients with no CVD and CKD patients who survived, respectively, most likely because of a higher prevalence of inflammation and malnutrition in the patients with CVD and those who died.

In agreement with many previous studies (5–11), plasma AA concentrations in CKD patients were altered compared with the concentrations in control subjects. Thus, the CKD patients in the present study had plasma AA abnormalities that are considered typical for CKD, ie, high plasma concentrations of several NEAAs and low concentrations of many EAAs. Inflammation may also have a role in the abnormal AA pattern seen in children with kwashiorkor, because the abnormal pattern of AAs in uremic patients resembles that seen in children with protein-energy malnutrition (19).

The present data clearly show that concentrations of most NEAAs and several EAAs are lower in CKD patients with inflammation than in CKD patients with no inflammation and that serum CRP concentrations are associated independently with low concentrations of AAs (Table 5Go). These findings suggest a significant effect of inflammation on AA concentrations. This hypothesis is additionally supported by the inverse relation between the concentrations of several AAs and some inflammatory markers. Moreover, a more marked reduction in AA concentrations was observed in CKD patients with both inflammation and malnutrition than in malnourished patients with no inflammation, and inflammation was independently associated with the observed alteration in the concentrations of several AAs (Table 3Go).

The findings in the present study suggest that inflammation could contribute to malnutrition in CKD patients by reducing the circulating pool of free AAs in patients with inflammation. However, the mechanisms by which inflammation lowers plasma AA concentrations in CKD patients are not clear. Evidence suggests that inflammation leads to increased losses of nitrogen in the urine, increased AA oxidation, and increased metabolic demands of AAs (12, 20–22).

Also, the systemic inflammatory response and accumulation of proinflammatory cytokines may contribute to lower AA concentrations in CKD patients through a variety of other mechanisms, such as inhibition of appetite, changes in gastrointestinal functions and carbohydrate metabolism, increased rate of muscle and protein breakdown, and insulin resistance (23–25). Recently, it was reported that the impairment of protein assimilation in uremic patients (26, 27) is associated with the malnutrition-inflammation-atherosclerosis syndrome (27). However, hyperinsulinemia, which is common in CKD patients, likely causes a shift of AAs from an extracellular to an intracellular compartment, which results in low plasma AA concentrations. In the present study, patients with inflammation had higher insulin concentrations than did patients with no inflammation, which may have contributed to the low plasma AA concentrations that were observed in that group of patients. Although insulin may increase extracellular AA transport into tissues, we have not identified any clinical study that confirms such an association. However, in the present study, we found that malnutrition, which was more prevalent in patients with inflammation, was associated with low concentrations of both insulin and AAs. This suggests that the low plasma AA concentrations in the patients with inflammation were not due solely to a difference in insulin concentrations.

Uremic patients are often anorexic, which leads to a reduced intake of protein. In addition, many patients in the present study were prescribed a protein-restricted diet that further contributed to the observed low intake of dietary protein, which was estimated from nPNA (Table 1Go). Therefore, a low protein intake, which was perhaps the consequence of inflammation, may have contributed to the abnormalities in AA concentrations observed in the present study. However, in the present study, no association was found between nPNA and AA concentrations.

After protein intake was normalized to SBW, lower protein intakes were observed in patients with inflammation and malnourished patients than in patients with no inflammation and nourished patients. This finding is similar to the findings in patients undergoing hemodialysis (28) and supports the concept that the use of actual body weight for the normalization of protein intake may be flawed and misleading (29, 30) because it yields inflated nPNA measurements in underweight and malnourished patients.

In the present study, fasting CKD patients with malnutrition had lower plasma concentrations of most AAs than did nourished patients, and the changes in BCAA concentrations as well as in the concentrations of several EAAs were more associated with malnutrition than with inflammation (Table 3Go). Not surprisingly, BCAA concentrations were associated with nutritional status. Dietary protein intake, insulin concentrations, and acid-base balance are important factors in BCAA metabolism. However, in the present study, no significant differences in BCAA concentrations were observed between patients with inflammation and patients with no inflammation, although patients with inflammation had lower protein intakes and higher insulin concentrations than did patients with no inflammation. Malnutrition has an influence on plasma AA concentrations in CKD patients (31), but the present study examined the extent to which this relation was independent of the effect of inflammation. As shown in Table 3Go, the presence of both inflammation and malnutrition in CKD patients was associated with a more marked reduction in AA concentrations than in the patients with only one of these conditions. However, the limited number in patients in the present study did not allow us to detect possible interactions between AA concentrations, nutritional status, and inflammation (Table 3Go).

CKD patients may experience ≥2 types of malnutrition (4): type 1 malnutrition is associated with anorexia because of the uremic syndrome per se, whereas type 2 malnutrition is mainly cytokine-driven and characterized by inflammation and protein catabolism. The association between malnutrition, inflammation, and atherosclerosis (4) suggests that patients with type 2 malnutrition also could have a higher prevalence of CVD than patients with type 1 malnutrition. In the present study, patients with both malnutrition and inflammation had a higher prevalence of CVDclin than did patients with only malnutrition or inflammation. Moreover, the plasma concentrations of EAAs and NEAAs were significantly lower in patients with CVDclin than in patients without CVDclin, which was probably due to the high prevalence of inflammation and malnutrition in the patients with CVDclin.

The inverse relation between plasma AA concentrations and the concentrations of inflammatory markers in CKD patients agrees with the findings in nonuremic subjects, which showed an immediate or long-standing reducing effect of AA supplementation on proinflammatory cytokine concentrations and on the systemic inflammatory response (15, 32–35). In CKD patients, oral AA supplements (8, 36–38) and AA-based peritoneal dialysis fluid (39) were used to provide additional AAs to improve protein and energy homeostasis. However, the effect of such AA supplementation on the acute or chronic systemic inflammatory response has not been systematically studied in CKD patients. Nonetheless, it was recently reported that oral EAA supplementation reduced CRP concentrations in patients undergoing hemodialysis (40). Such an effect, if confirmed, may add a new advantage for the use of AA supplements in CKD patients.

The present study showed that patients with higher AA concentrations have a better survival rate than do patients with lower AA concentrations (Figure 1Go). The higher prevalence of inflammation and malnutrition in the patients with lower total AA concentrations may partly explain the higher mortality rate in these patients than in the patients with higher total AA concentrations.

Some limitations of the present study should be considered. First, the findings were limited by the number of patients. Second, measurements in a single sample at a certain time may not reflect the natural course of the disease. Third, this was a post hoc analysis, which may limit the value of the study. Finally, the present study does not provide a mechanistic explanation of whether an inflammatory state causes low AA concentrations. Therefore, additional studies are needed to better understand the mechanisms by which a systemic inflammatory response in uremic patients may result in low concentrations of plasma AAs.

In conclusion, the present findings show, for the first time, an independent association between plasma AA concentrations and the concentrations of circulating inflammatory markers in fasting CKD patients. This suggests a possible role of inflammation as a cause of low plasma AA concentrations in uremic patients. Additional studies are needed to confirm these findings and to assess whether AA supplementation has a beneficial effect on inflammation, malnutrition, and outcome in uremic patients.


   ACKNOWLEDGMENTS
 
We acknowledge the skilled technical assistance of Monica Eriksson and Ann-Christin Bragfors-Helin.

MES, PS, PB, OH, AA, and BL were responsible for the study design. PS, PB, and OH were involved in the patient recruitment and the data collection. RP-F, ERA, and BA provided significant advice on the laboratory procedures. MES and ARQ were responsible for the statistical analyses, which were reviewed by JCDF, AA, and BL. MES wrote the manuscript, which was reviewed by all coauthors. JCDF and BL are affiliated with Baxter Healthcare Inc. None of the other authors had any conflicts of interest.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication February 1, 2005. Accepted for publication April 21, 2005.




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