Inflammation contributes to low plasma amino acid concentrations
in patients with chronic kidney disease1–3
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
ABSTRACT
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 ther-
apy. The nutritional status of these patients was assessed by a sub-
jective global assessment.
Results: The patients with inflammation [C-reactive protein (CRP)
concentrations 쏜10 mg/L] or malnutrition had lower AA concen-
trations 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 mal-
nutrition alone. Significant inverse correlations were observed be-
tween the plasma concentrations of most of the essential and non-
essential AAs and inflammatory markers, whereas serum albumin
concentrations were positively correlated with several AA concen-
trations. 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 associ-
ated 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. Am
J Clin Nutr 2005;82:342–9.
KEY WORDS Amino acids, cardiovascular disease, chronic
kidney disease, C-reactive protein, inflammation, malnutrition,
mortality
INTRODUCTION
Chronic kidney disease (CKD) is characterized by an excep-
tionally high mortality rate, primarily from cardiovascular dis-
ease (CVD). Chronic inflammation is a common feature in CKD
342 Am J Clin Nutr 2005;82:342–9. Printed in USA. © 2005 American Society for Clinical Nutrition
patients and is associated with atherosclerotic CVD through var-
ious pathogenetic mechanisms (1). Moreover, the prevalence of
protein-energy malnutrition in CKD patients is high, and inflam-
mation 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
Downloaded from ajcn.nutrition.org by guest on November 2, 2016
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 es-
sential 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 nutri-
tional 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 metabo-
lism (12), we hypothesized that the systemic inflammatory re-
sponse seen in a large proportion of CKD patients may contribute
to AA pattern disturbances.
The systemic inflammatory response stimulates protein catab-
olism (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 proin-
flammatory cytokines can cause anorexia and increased protein
catabolism, they represent an important cause of protein wasting
in CKD patients (16). Furthermore, proinflammatory cytokines
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 Karo-
linska Institute.
3
Reprints not available. Address correspondence to B Lindholm, the Di-
visions of Baxter Novum and Renal Medicine, Department of Clinical Sci-
ence, Karolinska University Hospital Huddinge, K-56, S-141 86 Stockholm,
Sweden. E-mail: bengt.lindholm@klinvet.ki.se.
Received February 1, 2005.
Accepted for publication April 21, 2005.
 INFLAMMATION AND AMINO ACIDS IN UREMIA
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 anal-
ysis 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
Subjects
The patients in the present study were included in a prospec-
tive cohort study of atherosclerosis and lipid metabolism in pa-
tients 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
(앐SD) body mass index (in kg/m2) was 25 앐 4. Exclusion cri-
teria were age 쏜70 y, liver dysfunction, diabetes mellitus, clin-
ical signs of intercurrent infection, and unwillingness to partic-
ipate in the study. Fifty-four (27%) patients had a clinical history
or signs of cerebrovascular, cardiovascular, or peripheral vascu-
lar 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 dis-
ease, and 2 had a history of an aortic aneurysm. One hundred
forty-three patients were studied before starting dialysis treat-
ment (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 medi-
cations 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 in-
formed 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 Stock-
holm region was performed by Statistics Sweden (SCB). No
343
other exclusion criteria, other than an unwillingness to partici-
pate 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 Ҁ70 °C until ana-
lyzed. 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 쏝10 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 ␣ and interleukin 6 were
measured with a photometric enzyme-linked immunosorbent as-
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say obtained from Boehringer Mannheim (Mannheim, Ger-
many). Plasma neopterin concentrations were measured with a
radioimmunoassay kit (Behring Diagnostic, Rueil-Malmaison,
France). The concentrations of both the soluble intracellular ad-
hesion molecule 1 and the soluble vascular cell adhesion mole-
cule 1 were measured (n ҃ 63 patients) with a commercially
available enzyme-linked immunosorbent assay kit (R&D Sys-
tems Europe Ltd, Abingdon, United Kingdom). A specific ra-
dioimmunoassay kit was used to analyze plasma insulin concen-
trations (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 inci-
dence 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 malnu-
trition, 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 ni-
trogen appearance (PNA), which was calculated from urea ki-
netic 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.
344 SULIMAN ET AL

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

CKD subgroup

Control subjects All CKD patients No inflammation2 Inflammation3

(n ҃ 11 F, 28 M) (n ҃ 80 F, 120 M) (n ҃ 51 F, 77 M) (n ҃ 29 F, 43 M)

Age (y) 68 (38–80)4 53 (22–70)5 48 (22–70) 61 (33–70)6

BMI (kg/m2) 25 앐 37 25 앐 4 24 앐 4 24 앐 4
nPNA8
(g · kg SBWҀ1 · dҀ1) — 0.69 앐 0.16 0.71 앐 0.16 0.65 앐 0.169
(g · kg ABWҀ1 · dҀ1) — 0.72 앐 0.17 0.73 앐 0.15 0.69 앐 0.17
GFR (mL/min)10 82.0 (61.0–118.0) 6.5 (0.8–16.1)5 6.8 (3.1–14.3) 5.9 (0.8–16.1)
Inflammation (%) — 36 0 100
Malnutrition (%) — 29 20 46
CVD (%) — 27 21 389
Insulin (␮IU/mL)11 5.8 (2.0–16.8) 14.3 (3.6–50.3)5 13.0 (3.6–49.3) 18.2 (4.6–50.3)12
Serum albumin (g/L) 39 앐 2 34 앐 65 35 앐 6 32 앐 55
Serum creatinine (␮mol/L) 82 앐 17 748 앐 2505 767 앐 252 713 앐 245
CRP (mg/L) 1.2 (0.2–32.0) 9 (9–134)5 쏝10 23 (10–134)6
Fibrinogen (g/L)13 2.9 (2.0–4.8) 4.6 (2.2–11.2)5 4.3 (2.2–9.7) 5.5 (2.3–11.2)6
IL-6 (pg/mL)14 2.0 (0.4–10.0) 5.8 (0.8–44.9)5 3.8 (0.8–36.6) 9.5 (3.1–44.9)6

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TNF-␣ (pg/mL)15 3.8 (1.6–10.6) 9.6 (3.8–81.8)5 9.1 (3.8–34.2) 11.3 (4.9–81.8)6
Neopterin (ng/mL)16 — 101 (15–1228) 86 (15–389) 143 (34–1228)12
1
CRP, C-reactive protein; nPNA, normalized protein equivalent of nitrogen appearance; GFR, glomerular filtration rate; CVD, cardiovascular disease;
IL-6, Interleukin 6; TNF-␣, Tumor necrosis factor ␣; SBW, standard body weight; ABW, actual body weight.
2
Based on a CRP concentration 쏝10 mg/L.
3
Based on a CRP concentration 욷10 mg/L.
4
Median; range in parentheses (all such values).
5
Significantly different from control subjects, P 쏝 0.001 (Student’s unpaired t test).
6 ,9 ,12
Significantly different from CKD patients with no inflammation (Student’s unpaired t test, Mann-Whitney U test, or chi-square test, as appropriate):
6
P 쏝 0.001, 9 P 쏝 0.05, 12 P 쏝 0.01.
7
x៮ 앐 SD (all such values).
8
n ҃ 166.
10
n ҃ 170.
11
n ҃ 196.
13
n ҃ 150.
14
n ҃ 169.
15
n ҃ 151.
16
n ҃ 115.

Within the follow-up period, 40 (20%) patients died and 80 Kaplan-Meier test. All analyses were performed with the use of
(40%) patients received kidney transplants. statistical software SAS version 9.1 (SAS Inc, Cary, NC).

Statistical analyses
Values were expressed as medians (ranges) or means (앐SDs),
as appropriate. A P value 쏝 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 vari-
ables with a chi-square test. Spearman’s rank correlation (␳) was
used to assess the correlations between 2 variables. The differ-
ence between 4 groups was analyzed with the Kruskal-Wallis
analysis of variance (ANOVA). To measure the degree of asso-
ciation between variables, a Wilks lambda 2-factor ANOVA was
used. The model included a test for the effect of order. A gener-
alized 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 anal-
ysis was used to assess the predictors for the sum of EAA con-
centrations, the sum of NEAA concentrations, and the sum of all
AA concentrations. A survival analysis was made with the
RESULTS
The clinical and biochemical characteristics of the control
subjects and the patients studied are shown in Table 1. 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.
The patients were divided into 2 groups on the basis of inflam-
matory status (2): patients with CRP concentrations 쏝10 mg/L
were classified as having no inflammation (n ҃ 128), and pa-
tients with CRP concentrations 욷10 mg/L were classified as
having inflammation (n ҃ 72; Table 1). The patients with a
concentration of CRP 욷10 mg/L were older and had a higher
prevalence of both malnutrition (46% compared with 20%; P 쏝
 INFLAMMATION AND AMINO ACIDS IN UREMIA 345
TABLE 2 lysine, methionine, and tryptophan were also significantly lower
Comparison between plasma amino acid (AA) concentrations in healthy in the patients with inflammation than in the patients without
control subjects and chronic kidney disease (CKD) patients1 inflammation.
Control subjects (n ҃ 39) CKD patients (n ҃ 200) Moreover, serum CRP concentrations were negatively corre-
lated with plasma concentrations of asparagine, serine, glycine,
␮mol/L
citrulline, arginine, alanine, histidine, threonine, lysine, methio-
NEAA
nine, and tryptophan and were also negatively correlated with the
Glutamic acid 33 (9–89) 43 (9–342)2
Asparagine 43 (22–61) 49 (15–97)2 sum of NEAA concentrations, the sum of EAA concentrations,
Serine 88 (60–149) 93 (40–214) and the sum of all AA concentrations [␳ range: Ҁ0.16 (P 쏝 0.05)
Glutamine 633 (364–1013) 567 (299–1010)3 to Ҁ0.40 (P 쏝 0.0001)].
Glycine 215 (125–392) 261 (103–742)3 Interleukin 6 concentrations (n ҃ 169) were negatively cor-
Citrulline 40 (25–76) 84 (23–209)3 related with plasma concentrations of asparagine, serine, gly-
Arginine 80 (39–130) 89 (10–209)4 cine, citrulline, alanine, histidine, tyrosine, and tryptophan and
Alanine 313 (126–610) 317 (84–736) with the sum of NEAA concentrations and the sum of all AA
Taurine 40 (22–62) 57 (13–188)3 concentrations [␳ range: Ҁ0.15 (P 쏝 0.05) to Ҁ0.28 (P 쏝 0.01)].
Ornithine 38 (4–93) 80 (6–226)3
Serum concentrations of tumor necrosis factor ␣ (n ҃ 151)
EAA
showed negative correlations with citrulline, arginine, alanine, his-
Histidine5 79 (49–120) 74 (12–151)
Threonine 130 (50–225) 103 (50–246)4 tidine, threonine, tryptophan, valine, isoleucine, and leucine con-
Tyrosine5 61 (37–108) 39 (18–91)3 centrations and with the sum of branched-chain AA (BCAA) con-
Lysine 148 (90–220) 152 (61–286) centrations, the sum of EAA concentrations, and the sum of all AA

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Methionine 22 (12–44) 23 (11–83) concentrations [␳ range: Ҁ0.16 (P 쏝 0.05) to Ҁ0.25 (P 쏝 0.01)].
Tryptophan 44 (29–67) 21 (11–101)3 Serum fibrinogen concentrations (n ҃ 150) were also nega-
Phenylalanine 52 (34–68) 53 (28–168) tively correlated with the concentrations of asparagine, serine,
Valine 217 (151–307) 156 (64–398)3 glutamine, glycine, citrulline, arginine, alanine, histidine, thre-
Isoleucine 53 (26–76) 57 (23–149) onine, lysine, and methionine and with the sum of NEAA concen-
Leucine 109 (64–156) 64 (22–178)3
trations, the sum of EAA concentrations, and the sum of all AA
Sum of NEAAs 1559 (842–2384) 1665 (950–2802)4
Sum of BCAAs 379 (246–532) 284 (133–550)3
concentrations [␳ range: Ҁ0.16 (P 쏝 0.05) to Ҁ0.38 (P 쏝 0.0001)].
Sum of EAAs 901 (588–1242) 748 (400–1412)3 Furthermore, serum neopterin concentrations (n ҃ 115) were
Sum of AAs 2462 (1430–3625) 2440 (1350–4214) negatively correlated with concentrations of asparagine, citrul-
NEAAs/EAAs 1.7 (1.3–2.3) 2.2 (1.3–4.2)3 line, arginine, threonine, lysine, tryptophan, and valine and with
1 the sum of NEAA concentrations and the sum of all AA concen-
All values are medians; range in parentheses. NEAA, nonessential
AA; BCAA, branched-chain AA; EAA, essential AA.
trations [␳ range: Ҁ0.19 (P 쏝 0.05) to Ҁ0.27 (P 쏝 0.01)]. Serum
2–4
Significantly different from control subjects (Mann-Whitney U soluble intracellular adhesion molecule 1 and soluble vascular
test): 2 P 쏝 0.01, 3 P 쏝 0.001, 4 P 쏝 0.05. cell adhesion molecule 1 concentrations were negatively corre-
5
Thought to be an EAA in uremia. lated with the concentrations of arginine, ornithine, tryptophan,
valine, and isoleucine [␳ range: Ҁ0.27 (P 쏝 0.05) to Ҁ0.35 (P 쏝
0.01)], whereas the inverse correlations with threonine (␳ ҃
0.001) and CVDclin (38% compared with 21%; P 쏝 0.05) than did Ҁ0.25, P ҃ 0.06), histidine (␳ ҃ Ҁ0.24, P ҃ 0.06), and phenyl-
the patients with a CRP concentration 쏝10 mg/L; however, sex, alanine (␳ ҃ Ҁ0.24, P ҃ 0.06) were not statistically significant.
body mass index, and GFR were not significantly different be- Serum albumin concentrations were positively correlated with
tween the 2 patient groups. As expected, the serum concentra- the concentration of most AAs, including asparagine, glycine,
tions of albumin and inflammatory markers differed between the citrulline, arginine, alanine, ornithine, histidine, threonine, ty-
2 groups. The nPNA was significantly lower in patients with rosine, lysine, methionine, tryptophan, phenylalanine, and valine
inflammation than in patients with no inflammation when nPNA and with the sum of NEAA concentrations, the sum of EAA
was normalized to SBW; however, no significant differences concentrations, and the sum of all AA concentrations [␳ range:
were seen between the 2 patient groups when nPNA was nor- 0.16 (P 쏝 0.05) to 0.35 (P 쏝 0.0001)]. However, we unex-
malized to ABW (Table 1). Serum insulin concentrations were pectedly found that nPNA was not correlated with AA con-
significantly higher in the patients with inflammation than in the centrations.
patients with no inflammation (Table 1) and were lower in mal- Twenty-nine percent of the patients were found to be malnour-
nourished than in nourished patients [11.5 (3.7–33.4) and 15.3 ished when nutritional status was assessed by SGA (n ҃ 196; data
(3.6 –50.3) ␮IU, respectively; P 쏝 0.01]. were not available for 4 patients; Table 1). Thirty-two of the
The plasma concentrations of 7 NEAAs from fasting subjects malnourished patients (56%) had inflammation, whereas 38
were significantly higher in the CKD patients than in the control (27%) of the patients with normal nutritional status had inflam-
subjects, whereas the plasma concentrations of 5 EAAs and glu- mation. The plasma concentrations of all EAAs (except ty-
tamine were significantly lower (Table 2). The other AA con- rosine), a few NEAAs, and NEAA/EAA were significantly lower
centrations were not significantly different between the patients in the malnourished patients than in the patients with normal
and the control subjects. nutritional status (data not shown). In addition, nPNA was sig-
Compared with the 128 patients without inflammation, the 72 nificantly lower in the malnourished patients than in the patients
patients with inflammation had significantly lower concentra- with normal nutritional status when nPNA was normalized to
tions of 7 NEAAs but not of glutamic acid, taurine, or ornithine. SBW (0.63 앐 16 compared with 0.71 앐 16 g · kg SBWҀ1 · dҀ1,
Of the EAAs, the plasma concentrations of histidine, threonine, P 쏝 0.01), whereas nPNA was similar between the malnourished
346 SULIMAN ET AL

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

Group
␮mol/L
1 2 3 4
(n ҃ 101) (n ҃ 25) (n ҃ 38) (n ҃ 32) Significant main effects2

NEAA
Glutamic acid 43 (9–342) 42 (11–107) 47 (11–243) 45 (13–166) —
Asparagine 52 (29–97) 52 (31–66) 43 (15–92) 37 (27–77) A, B
Serine 95 (45–214) 99 (55–147) 85 (46–130) 82 (40–139) B
Glutamine 592 (299–1010) 571 (415–791) 516 (203–807) 526 (311–830) B
Glycine 285 (129–742) 263 (103–466) 225 (117–398) 239 (130–597) A, B
Citrulline 90 (47–209) 85 (38–139) 77 (29–181) 67 (23–137) B
Arginine 92 (10–209) 101 (47–181) 84 (44–175) 70 (34–181) B
Alanine 341 (137–736) 271 (171–527) 299 (110–513) 267 (84–486) A, B
Taurine 57 (17–130) 59 (31–133) 56 (12–148) 48 (13–188) —
Ornithine 81 (28–176) 80 (31–112) 85 (6–226) 72 (38–177) —
EAA
Histidine3 82 (12–146) 70 (46–97) 75 (36–151) 63 (37–122) A, B

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Threonine 122 (50–246) 104 (55–232) 104 (51–238) 81 (51–204) A, B
Tyrosine3 37 (19–71) 39 (23–55) 41 (20–91) 36 (18–62) —
Lysine 158 (82–286) 151 (61–238) 150 (87–235) 133 (84–223) A
Methionine 25 (11–83) 22 (11–41) 24 (8–46) 22 (9–41) A
Tryptophan 23 (11–101) 21 (12–40) 21 (9–46) 20 (10–38) —
Phenylalanine 53 (32–113) 51 (36–71) 56 (34–88) 51 (28–169) —
Valine 161 (76–310) 142 (68–202) 165 (84–287) 132 (64–398) A
Isoleucine 61 (30–149) 54 (28–73) 61 (23–102) 51 (28–113) A
Leucine 67 (25–165) 65 (38–110) 59 (22–178) 58 (24–168) —
Sum of NEAAs 1777 (998–2802) 1694 (1140–2179) 1560 (958–2243) 1563 (950–2267) B
Sum of BCAAs 293 (133–529) 255 (138–338) 300 (170–502) 230 (137–550) A
Sum of EAAs 806 (471–1412) 728 (474–879) 741 (492–1187) 621 (400–1081) A
Sum of AAs 2546 (1581–4214) 2433 (1844–3011) 2305 (1495–3318) 2209 (1350–3169) A, B
NEAAs/EAAs 2.2 (1.7–4.2) 2.4 (1.4–3.6) 2.1 (1.4–3.1) 2.4 (1.6–2.8) A
1
All values are medians; ranges in parentheses. Nutritional status was assessed in 196 patients. NEAA, nonessential AA; BCAA, branched-chain AA;
EAA, essential AA.
2
Two-factor ANOVA for malnutrition (A) and inflammation (B). There were no significant interactions between the 2 variables.
3
Thought to be an EAA in uremia.

and nourished patients when it was normalized to ABW (0.72 앐
18 compared with 0.72 앐 15 g · kg ABWҀ1 · dҀ1).
The patients who underwent SGA (Table 3; 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) in-
cluded patients who had both inflammation and malnutrition.
Using a one-factor ANOVA, we found that the plasma concen-
trations of asparagine, serine, glutamine, glycine, citrulline, ar-
ginine, 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 be-
tween the 4 patient groups; patients in group 4 had the lowest AA
concentrations. A further analysis by 2-factor ANOVA (Table 3)
showed that several AAs were associated with inflammation as
well as with malnutrition. However, none of the AAs showed
significant malnutrition ҂ inflammation interactions.
When the CKD patients were divided into 2 groups on the basis
of the presence of CVDclin (Table 4), the plasma concentrations
of glutamic acid, aspartic acid, alanine, histidine, threonine, me-
thionine, and tryptophan and the sum of NEAA concentrations,
the sum of EAA concentrations, and the sum of all AA concen-
trations were significantly lower in the patients with CVDclin than
in the patients with no CVDclin.
A stepwise multivariate regression analysis was used to de-
termine the factors that were associated with plasma AA con-
centrations (Table 5) 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.
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 ␮mol/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 1).
 INFLAMMATION AND AMINO ACIDS IN UREMIA 347
TABLE 4 TABLE 5
Plasma amino acid (AA) concentrations in the chronic kidney disease Stepwise multivariate regression analysis of predictors of plasma amino
patients with and without clinical cardiovascular disease (CVD)1 acid (AA) concentrations in chronic kidney disease patients1

Without CVD (n ҃ 146) With CVD (n ҃ 54) Estimate SE P

␮mol/L Predictors of the sum of NEAAs 2

NEAA Intercept 1278.7 172.6 쏝0.0001

Glutamic acid 46 (9–342) 40 (11–139)2 Sex, male and female 77.5 25.8 쏝0.01
Asparagine 50 (15–97) 45 (30–92)2 Serum albumin (g/L) 14.4 4.7 쏝0.01
Serine 95 (40–214) 84 (53–155) Serum CRP (mg/L) Ҁ4.8 1.3 쏝0.001
Glutamine 562 (203–1010) 568 (361–968) Predictors of the sum of EAAs3
Glycine 263 (103–638) 244 (117–742) Intercept 567.6 66.6 쏝0.0001
Citrulline 84 (29–209) 84 (23–157) Sex, male and female 40.8 11.9 쏝0.001
Arginine 90 (34–209) 85 (10–181) SGA, normal and 39.7 13.2 쏝0.01
Alanine 329 (84–736) 280 (126–625)3 malnourished
Taurine 57 (12–187) 50 (17–188) Serum albumin (g/L) 5.4 2.0 쏝0.01
Ornithine 81 (6–226) 76 (31–165) Predictors of the sum of all AAs4
EAA Intercept 1733.7 202.1 쏝0.0001
Histidine4 78 (31–146) 66 (12–151)3 Sex, male and female 123.5 39.4 쏝0.01
Threonine 108 (50–246) 90 (51–241)3 Serum albumin (g/L) 17.4 7.3 쏝0.05
Tyrosine4 39 (18–91) 37 (20–76) Serum CRP, (mg/L) Ҁ5.5 2.1 쏝0.05
Lysine 153 (61–286) 149 (84–264) GFR (mL/min) 36.5 18.0 쏝0.05

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Methionine 25 (9–83) 21 (11–48)3 1
Variables known to influence plasma AA concentrations [sex, age,
Tryptophan 23 (10–101) 20 (11–40)2
glomerular filtration rate (GFR), subjective global assessment (SGA), albu-
Phenylalanine 53 (28–169) 53 (34–83)
min, and insulin] and serum C-reactive protein (CRP) as a marker of inflam-
Valine 158 (64–398) 144 (72–310)
mation) were included in the initial models. SGA was entered in the model as
Isoleucine 60 (23–149) 54 (32–105)
a categorical variable with 2 categories: SGA ҃ 1 (nourished) and SGA 쏜1
Leucine 63 (22–178) 66 (33–168)
(malnourished). No significant interactions were observed in the 3 models.
Sum of NEAAs 1697 (950–2667) 1599 (1047–2802)2
NEAA, nonessential AA; EAA, essential AA.
Sum of BCAAs 290 (132–550) 255 (167–529) 2
Total adjusted r2 ҃ 0.24.
Sum of EAAs 771 (400–1229) 700 (492–1412)2 3
Total adjusted r2 ҃ 0.15.
Sum of AAs 2488 (1350–3868) 2295 (1593–4214)2 4
Total adjusted r2 ҃ 0.20.
NEAAs/EAAs 2.2 (1.3–4.2) 2.2 (1.4–3.3)
1
All values are medians; ranges in parentheses. NEAA, nonessential
AA; BCAA, branched-chain AA; EAA, essential AA. with kwashiorkor, because the abnormal pattern of AAs in ure-
2 ,3
Significantly different from patients with CVD (Mann-Whitney U mic patients resembles that seen in children with protein-energy
test): 2 P 쏝 0.05, 3 P 쏝 0.01. malnutrition (19).
4
Thought to be an EAA in uremia. The present data clearly show that concentrations of most
NEAAs and several EAAs are lower in CKD patients with in-
flammation than in CKD patients with no inflammation and that
serum CRP concentrations are associated independently with
DISCUSSION
low concentrations of AAs (Table 5). These findings suggest a
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 inflam-
mation. The concentrations of most plasma AAs correlated in-
versely 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 mal-
nourished 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 FIGURE 1. The survival rate of patients with chronic kidney disease over
present study had plasma AA abnormalities that are considered a 5-y follow-up with regard to all-cause mortality and in relation to the
median plasma concentration (2440 ␮mol/L) of total amino acids (AAs) at
typical for CKD, ie, high plasma concentrations of several the start of renal replacement therapy. The Kaplan-Meier survival curves
NEAAs and low concentrations of many EAAs. Inflammation show that the patients with high AA concentrations had better survival rates
may also have a role in the abnormal AA pattern seen in children than did the patients with low AA concentrations. Log-rank ҃ 4.2, P 쏝 0.05.
348 SULIMAN ET AL
significant effect of inflammation on AA concentrations. This
hypothesis is additionally supported by the inverse relation be-
tween the concentrations of several AAs and some inflammatory
markers. Moreover, a more marked reduction in AA concen-
trations was observed in CKD patients with both inflamma-
tion and malnutrition than in malnourished patients with no
inflammation, and inflammation was independently associ-
ated with the observed alteration in the concentrations of
several AAs (Table 3).
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. How-
ever, 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 con-
centrations in CKD patients through a variety of other mecha-
nisms, 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, hyper-
insulinemia, which is common in CKD patients, likely causes a
shift of AAs from an extracellular to an intracellular compart-
ment, 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 associ-
ated with low concentrations of both insulin and AAs. This sug-
gests that the low plasma AA concentrations in the patients with
inflammation were not due solely to a difference in insulin con-
centrations.
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 esti-
mated from nPNA (Table 1). 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 associa-
tion was found between nPNA and AA concentrations.
After protein intake was normalized to SBW, lower protein
intakes were observed in patients with inflammation and mal-
nourished 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 3). Not surprisingly,
BCAA concentrations were associated with nutritional status.
Dietary protein intake, insulin concentrations, and acid-base bal-
ance are important factors in BCAA metabolism. However, in the
present study, no significant differences in BCAA concentra-
tions were observed between patients with inflammation and
patients with no inflammation, although patients with inflamma-
tion had lower protein intakes and higher insulin concentrations
than did patients with no inflammation. Malnutrition has an in-
fluence 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 3,
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 condi-
tions. 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 3).
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CKD patients may experience 욷2 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, inflamma-
tion, 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 inflam-
mation. 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 supplemen-
tation 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 dial-
ysis 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 supplemen-
tation reduced CRP concentrations in patients undergoing he-
modialysis (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 con-
centrations have a better survival rate than do patients with lower
AA concentrations (Figure 1). The higher prevalence of inflam-
mation 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 concen-
trations.
Some limitations of the present study should be considered.
First, the findings were limited by the number of patients. Sec-
ond, measurements in a single sample at a certain time may not
reflect the natural course of the disease. Third, this was a post hoc
 INFLAMMATION AND AMINO ACIDS IN UREMIA
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 ure-
mic 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. Addi-
tional studies are needed to confirm these findings and to assess
whether AA supplementation has a beneficial effect on inflamma-
tion, malnutrition, and outcome in uremic patients.
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 proce-
dures. 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.
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