Transcript Microinflammation and...

Effects of low-grade chronic
inflammation on skeletal muscle
protein metabolism in patients with
CKD
Giacomo Garibotto
Genoa University, Division of Nephrology, Dialysis and Transplantation
Renal Discoveries
Grant Winners Meeting
Lake Bluff
December 4-5, 2005
Background (1)
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Several studies have shown a strong association
between chronic inflammation and long-term
mortality and morbidity in ESRD patients.
Indexes of both nutritional status and physical
function are linked to mortality in this population.
The percentage of patients showing evidence of
inflammation increases progressively along with
the decline in renal function, suggesting that cell
release and/or body removal of pro-inflammatory
cytokines is altered by uremia and/or treatment.
Background (2)
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Pathogenic mechanisms linking chronic
kidney disease, inflammation and
malnutrition not completely understood.
Also sites and mechanisms responsible for
the regulation of circulating pro
inflammatory cytokines in humans
currently poorly known.
Research protocol designed to address the
following questions in CKD patients:
1) Does low-grade chronic inflammation affect
muscle protein synthesis or degradation and thus
the control of net protein balance?
2) Is muscle skeletal energy expenditure increased
by microinflammation?
3) Is the response to anabolic hormones blunted by
microinflammation?
4) Do peripheral tissues release pro-inflammatory
cytokines into the circulation and therefore
contribute to the systemic inflammatory
response?
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Stenvinkel et al 2003
Adipose tissue and muscle-derived proteins
known to affect inflammation
Adipocyte
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TNF-α
IL-6
IL-1beta
leptin
adiponectin
SAA3
Pentraxin-3
IL-1ra
Macrophage migrator
inhibitor factor
Skeletal muscle
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TNF-α
IL-6
IL.8
IL-10
TNFrsI
TNFrsII
Immunostaining for IL-6
In skeletal muscle (Pedersen 2003)
Resting
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Exercising
IL-6 mRNA is expressed
in resting human muscle
and is rapidly increased by
contraction. A release of
IL-6 from the legs (which
are mainly composed of
skeletal muscle) has been
shown to take place during
physical
exercise
or
glycogen
depletion
(Febbraio 2004).
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In addition, insulin increases IL-6 gene
expression in insulin-resistant, but not in
healthy skeletal muscle (Carey 2003) and Il-6 is
released by muscle forearm in obese type 2
diabetic subjects (Corpeleijn JCEM 2005)
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Both reactive oxygen species and bacterial
infections (Lang 2003) can upregulate muscle
IL-6, likely because of an activation of nuclear
factor NF kB.
Aims of the study
To explore the hypothesis that some inflammatory
cytokine could be locally produced in skeletal muscle
and exported to other tissues.
First, we studied the exchange of cytokines
across the forearm in patients with CRF and in
hemodialysis-treated patients with ESRD.
Second, we performed an analysis of cytokine
protein and mRNA expression in muscle.
Protocols and methods: Forearm
exchange of cytokines
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31 patients studied. Sixteen patients with moderate
to severe CKD (estimated GFR=24±2 ml/min; CRP
12±3 mg/l; HCO3- 22.0±0.90 mol/l); 15 patients were
on HD (CRP 35±8 mg/l; HCO3- 23.2±0.9 mmol/l)
and studied after approximately 72 to 74 h from the
last dialytic treatment.
Triplicate sets of arterial and venous samples taken
across the forearm at 20-min intervals for TNF-α, IL6, IL-10 and IL-1 determinations,the postabsorptive
state.
Measure of forearm blood flow.
Plasma cytokine levels determined in triplicate by
ELISA (Diaclone, France)
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Age (yrs)
Body weight (Kg)
BMI (Kg/m2)
Fat-free mass (Kg)
Fat mass (Kg)
nPNA (g/kg)
albumin (g/dl)
BUN (mg/dl)
CKD
66±2
73±4
26±1
49±2
25±2
0.90±0.1
3.5±0.03
61±5
HD
67±3
68±4
24±1
46± 8
21±2
1±0.1
3.4±0.1
84±8
TNF-α A-V differences across the
forearm in CRF and HD patients
1,2
NS
NS
1
HD
CRF
0,8
pg/ml
0,6
0,4
0,2
0
ARTERY
VEIN
ARTERY
VEIN
Il-6 A-V differences across the
forearm in CRF and HD patients
P<0.005
90
80
70
CRF
HD
P<0.01
60
50
pg/ml
40
30
20
10
0
ARTERY
VEIN
ARTERY
VEIN
Peripheral tissues release IL-6 in patients
showing evidence of inflammation
2
0
pg/min.100 ml
-2
-4
-6
*
-8
All
Low IL-6 (<5pg/ml)
High IL-6(>5pg/ml)
-10
*
-12
-14
-16
Controls(6)
CRF (16)
HD (15)
*
100
Arterial Il-6 (pg/ml)
R=0.652;p<0.001
50
0
-2
18
Il-6 release from peripheral tissues
(pg/min.100 ml)
Relationship between release of IL-6
from peripheral tissues and plasma CRP
Il-6 release from
peruphery (pg/min.100ml)
30
20
R=0.79;p<0.001
10
0
0
20
40
60
80
CRP (mg/l)
100
120
140
160
Oxygen uptake by the forearm in patients with CKD and in controls
O2 uptake
20
NS
P= NS
ml/min.100ml
15
10
5
0
HD
HD
CKD
(all subjects)
(IL-6>5 pg/ml)
(all subjects)
HD
CKD
CKD (IL-6>5 ...
Controls
(IL-6<5 pg/ml)
(IL-6<5 pg/ml)
Phe release (nmol/min.100 ml)
0
-16
-18
(12)
-14
(15)
(8)
(7)
NS
(15)
(8)
HD
(IL-6>5 pg/ml)
HD
(IL-6<5 pg/ml)
HD
(all subjects)
CKD
(IL-6>5 pg/ml)
CKD
(IL-6<5 pg/ml)
CKD
(all subjects)
Controls
Net protein balance across the forearm in CKD and HD patients
-2
-4
-6
-8
-10
-12
<0.05
(7)
Relationship between net protein
breakdown and forearm IL-6 release
in CRF patients
Forearm IL-6 release (pg/min .100
ml)
26
r = 0.3861 p NS
24
22
20
18
16
14
12
10
8
6
4
2
0
-2
-4
6
8
10
12
14
16
Net Protein breakdown (nmol/min .100 ml)
18
Relationship between net protein breakdown
and forearm IL-6 release in HD patients
26
r = 0.594 p < 0.0194
forearm IL-6 release )pg/min.100 ml)
24
22
20
18
16
14
12
10
8
6
4
2
0
-2
-4
2
4
6
8
10
12
14
16
18
Net Protein Breakdown (nmol/min.100 ml)
20
22
24
Protocols and Methods:
Studies on muscle biopsies
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Muscle biopsies obtained from rectus
abdominis of 15 “inflamed” ESRD patients
(7M-8F, age:69±7 yrs, GFR 8.4±1 ml/min )
during the placement of a PD catheter and
in healthy subjects (4M-5F age 62±5yrs)
during surgery for abdominal wall hernias.
Immunohistochemical staining for human
IL-6.
Measurement of IL-6 mRNA in muscle
biopsies by semiquantitative RT-PCR.
Expression of IL-6/Bactin mRNA
IL-6/βactin mRNA expression in muscle of
control subjects and ESRD patients
* P=0.018
0,25
0,2
0,15
0,1
0,05
0
Control subjects
ESRD
(IL-6=2±1 pg/ml)
(IL-6=12±3pg/ml)
Immunohistochemical staining for IL-6 in skeletal
muscle
*
25
20
15
10
ESRD
Controls
5
Control
IL-6
0
ESRD
Myostatin
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Myostatin, a member of
TGF-β family of signaling
molecules
Myostatin blockade:
excessive growth and
increased force generation
of skeletal muscle
A role of myostatin in
regulation of fiber size and
cell survival in adult
skeletal muscle.
Hyperexpressed in AIDS
wasting
Belgian Blue
Mutation in myostatin gene
expression of myo/bact mRNA
Myostatin/βactin mRNA expression in
muscle of controls and ESRD patients
* P=0.015
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0,0
Control subjects
(IL-6=2±1 pg/ml)
ESRD
(IL-6=12±3pg/ml)
Muscle myostatin:
immunohistochemistry (Rectus abdominis )
35
30
*
*
25
20
15
ESRD
Controls
10
5
ESRD
0
Control
muscle myostatin/beta-actin mRNA
Relationship between IL-6 and myostatin
gene expressions in rectus abdominis
muscle of ESRD patients
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0
r=0.43, p=0.036
0
0,1
0,2
0,3
muscle IL-6/beta-actin mRNA
0,4
0,5
In conclusion, in renal patients with
evidence of microinflammation (I)
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Peripheral tissues release IL-6 into the
circulation and the release of IL-6 from
periphery is a major determinant of IL-6
levels.
Net protein breakdown is increased with
respect to non-inflamed patients. This
appears to be valid for HD but not for CRF
patients.
In conclusion, in renal patients with
evidence of microinflammation (II)
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Il-6 and myostatin protein and gene expressions
are both upregulated in skeletal muscle.
These results suggest that the magnitude of
increases in inflammatory cytokines in uremia may
be predictive of upregulation of muscle Il-6
synthesis and growth.
Given the possible systemic and local effects of IL6, peripheral tissues could play the double role of
victim and culprit of the inflammatory response in
HD patients.
IL-1,
Ca++,
Glycogen depletion
?
Fat cells
Skeletal muscle
Atrophy?
Lipolysis
Circulating IL-6
Endothelial damage
Glicogenolysis
Liver
Research protocol designed to address the
following questions in CKD patients:
1) Does low-grade chronic inflammation affect
muscle protein synthesis or degradation and thus
the control of net protein balance?
2) Is muscle skeletal energy expenditure increased
by microinflammation?
3) Is the response to anabolic hormones blunted by
microinflammation?
4) Do peripheral tissues release pro-inflammatory
cytokines into the circulation and therefore
contribute to the systemic inflammatory
response?
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Protocols and Methods:
Studies on forearm muscle protein
turnover
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Study of muscle protein turnover performed in the
postabsorptive state (Garibotto KI 1994).
At 7.00 a.m., a forearm vein cannulated and used
for a primed-continuous infusion of 2Hphenylalanine.
Catheters inserted into a brachial artery and in a
retrograde manner into the ipsilateral, deep
forearm vein.
Triplicate sets of arterial and venous samples
taken across the forearm at 20-min intervals after
150 min tracer equlibration period
Measure of blood flow by strain gauge
plethysmography
Muscle protein turnover rates:
CRF (n=21) and HD (n=18) patients
CONTROLS
CRF
HD
50
40
30
20
10
0
-10
-20
-30
nmol/min.100-40
ml
-50
Protein
degradation
Protein synthesis
Net protein
balance
Muscle protein turnover rates:
inflamed (n=11) vs non-inflamed (n=10)
CRF patients
INFLAMED
50
40
30
20
10
0
-10
-20
-30
-40
-50
NON INFLAMED
NS
NS
NS
Protein Degradation
Protein synthesis
Net Protein Balance
Muscle protein turnover rates:
inflamed (n=8) vs non-inflamed (n=10)
HD patients
INFLAMED
50
40
30
20
10
0
-10
-20
-30
-40
-50
NON INFLAMED
*
*
NS
Protein degradation
Protein Synthesis
Net Protein balance
EFFICIENCY BY MUSCLE PROTEIN TURN OVER
IN HD PATIENTS : INFLAMED VS. NON
INFLAMED
MUSCLE
PS
MUSCLE
PD
32% lost
NON-INFLAMED
PS
PD
53% lost
INFLAMED
Research protocol designed to address the
following questions in CKD patients:
1) Does low-grade chronic inflammation affect
muscle protein synthesis or degradation and thus
the control of net protein balance?
2) Is muscle skeletal energy expenditure increased
by microinflammation?
3) Is the response to anabolic hormones blunted by
microinflammation?
4) Do peripheral tissues release pro-inflammatory
cytokines into the circulation and therefore
contribute to the systemic inflammatory
response?
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Growth Hormone (GH) exerts several physiologic
and pharmacologic effects on protein, Na+, K+ and
energy metabolism.
Acute effects are caused by GH binding to its own
receptors, while chronic changes are mainly due to
the release of IGF-I.
Potential interactions of signaling elements serving
the growth hormone (GH), IL-6, and IGF-I receptors
(Haddad AJP 2004).
Aim of the study
To evaluate if the microinflammatory state
associated with uremia causes a resistance
to the acute actions of GH regarding K+ and
amino acid metabolism
Patients and Methods (I)
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16 patients with advanced chronic renal failure (Creat.clear
10-16 ml/min).
No history or evidence of infection, liver disease or neoplasia
Calorie intake about 28-32 Kcal/kg; protein intake
0.8-1.1 g/kg
Eight patients with evidence of peripheral vascular or
cardiovascular disease and CRP > 10 mg/l on three
sequental determinations (Group A)
Eight patients with CRP levels persistently in the normal
range (< 10 mg/l) (Group B)
Study performed also in 6 healthy volunteers (5M/1F)
(Controls)
Patients and Methods(II)
Parameter
Group
Group
A
B
Age (yrs)
60± 4
63± 5
gender
8M/1F
8M/1F
23±3
23± 4
0.85±3
0.83±4
22±3
23± 2
10± 3
8± 3
BMI
(Kg/m2)
nPNA
(g/kg)
[HCO3]
(mmol/l)
Creat Clear
(ml/min/1.73m2)
Procedures
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Study performed in the postabsorptive, overnight fasted
state.
Arterialized samples for the measure of plasma hormones,
K+ and amino acid levels drawn from a dorsal hand vein at
the baseline (at –15 and 0 min) and at 30-min intervals
during a 300-min primed-continuous infusion of rhGH (0.6
U) (0.7 mU/min/Kg) (Genotropin®, Pharmacia; Stockholm,
Sweden) in the contralateral arm.
rhGH
-30 0
60
120
180
240
300
min
sampling
Methods
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Measure of blood amino acids and plasma
potassium, Ca++, acid-base as well as GH
(chemiluminescent IRMA assay and Immunofunctional
GH) (Strasburger JCEM 1996).
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Measure of plasma insulin, cortisol and
proinflammatory cytokines (Il-6, Il-1, TNF-α,
TNFrs-1).
Effects of rhGH infusion on GH levels
GH infusion
180
160
GH levels [mg/l]
140
120
100
GH IRMA group A
80
GH IRMA group B
IFGH group A
60
IFGH group B
40
20
0
0
30
90
180
minutes
240
270
Effects of rhGH infusion on plasma insulin
rhGH
15
NS
plasma insulin (U/L)
13
11
*
9
7
5
3
0
30
60
90
120
150
180
210
240
270
minutes
Group A
Group B
Controls
Effects of rhGH infusion on plasma K+
rhGH
plasma potassium [mEq/l]
6
NS
5,5
5
*
4,5
*
*
*
*
*
180
210
240
*
4
*
3,5
*
*
3
0
30
60
90
120
150
270
minutes
Group A
Group B
Controls
Effects of rhGH infusion on plasma [HCO3-]
rhGH
25
NS
[HCO3] [mEq/l]
24
23
NS
22
*
*
21
*
**
**
**
210
240
270
20
0
30
Group A
60
Group B
90
120
Controls
150
180
minutes
Acute effects of GH infusion on BCAA levels
GH infusion
360
340
BCAA [mmol/l]
320
300
*
*
280
260
240
*
Group A
*
*
*
*
*
*
*
*
*
Group B
220
Controls
200
0
30
60
90
120
150
180
210
240
270
minutes
Relationships between GH-induced changes in
plasma K+ at 180 min and selected parameters
Variable
r
P
BMI
age
Insulin
CRP
-0.07
0.361
-0.279
0.515
NS
0.015
NS
0.04
Il-1
Il-6
TNF-α
-0.276
0.543
0.200
NS
0.025
NS
TNFrs1
PTH
0.594
0.15
0.025
NS
Relationships between GH-induced changes in plasma
essential amino acids at 180 min and selected parameters
Variable
R
P
BMI
-0.65
<0.001
age
0.30
NS
Insulin
CRP
-0.30
0.569
NS
0.05
Il-1
Il-6
-0.276
0.58
NS
0.05
TNF-α
TNFrs1
Crear clear
0.230
0.36
-0.88
NS
NS
<0.001
Conclusions (I)
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RhGH infusion causes a significant decrease in K+
levels, with correction of hyperkalemia in noninflamed patients with CRF. This response is
maximal after three hours. The absolute decline in
K+ levels is similar to that observed in healthy
subjects.
The sensitivity to GH regarding amino acids is
delayed in non-inflamed patients with CRF;
however, the overall response is similar to controls.
Conclusions (II)
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The sensitivity to GH regarding both K+ and
amino acid metabolism is blunted in patients with
chronic kidney disease showing evidence of
inflammation.
In these patients responses regarding potassium
metabolism are predicted by age, CRP, plasma Il-6
and TNFrs-1 levels. Responses regarding amino
acid metabolism are predicted by BMI, CRP, Il-6
and residual renal function.
These data are consistent with a block in GH
signaling caused by age and microinflammation.
Does the human kidney remove
IL-6 from the circulation in
humans?
Inter-organ exchange of IL-6
(n=6 patients undergoing
venous catheterizations for diagnosis)
(ng/min.1.73 m2)
0,8
A-V gradient: 16%
0,7
0,6
A-V gradient: 7%
*
0,5
0,4
0,3
*
0,2
0,1
0
KIDNEY
SPLANCHNIC ORGANS
Removal of IL-6 by splanchnic organs+ kidney accounts for
~50% of the calculated (Mohamed –Alì JCEM 1997)
IL-6 production in humans
Kidney+Splanchnic removal
(mmol/min)
1
0
Released by adipocytes
Forearm balance studies
Antonella Sofia
Rodolfo Russo
Valeria Cappelli
Massimiliano Di Martino
Alice Tarroni
Muscle molecolar biology
Vanessa Procopio
Daniela Verzola
Leptin/granulocytes
Tomaso Barreca
Franco Dallegri
Luciano Ottonello
(DiMI)
Genoa University
Muscle Biopsies:
Stefano Saffioti
Franco De Cian
Francesca Aloisi
Homocysteine/IL-6
Maria Rita Sala
Barbara Villaggio
Alessandro Valli
Studies on GH sensitivity
Antonella Barreca,
Francesco Minuto (DiSEM)
Genoa University
Supported by The Baxter/ISN
Extramural Program 2002
Truncal fat mass as a contributor to inflammation
in end-stage renal disease (Axelsson, AJCN 2004)
Relationship between GH-induced changes in plasma
K+ and basal TNFrs-1 levels
TNFrs-1 (pg/ml)
0,2
0
35
55
75
95
115
135
plasma potassium [mEq/L]
-0,2
-0,4
-0,6
-0,8
-1
-1,2
-1,4
-1,6
-1,8
R=0.59;p<0.025
155
In conclusion, in patients with CKD:
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Prevalence of inflammation and altered nutrition
increase progressively along with the decline in
GFR.
Both proxies for inflammation and nutrition are
associated to a worse outcome.
The question whether inflammation contributes to
atherosclerotic cardiovascular disease and dialysis
causes inflammation remains in part unanswered.
Selective alterations can be ascribed to individual
cytokines. Anorexia is best accounted for TNF-α
levels, while Il-6 appears to be the best predictor
for resistance to anabolic factors (EPO and Growth
Hormone) and hypoalbuminemia.
In conclusion, in patients with CKD (II):
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Besides circulating cells and endothelia, somatic
cells (adipocytes and muscle cells) are also a
source of inflammatory cytokines.
In this regard, skeletal muscle appear to be both
culprit and victim of the inflammatory processes.
All these data are consistent with a different
concept of malnutrition, which is based not only
on reduced nutrient intake but on overall
dysregulation, involving both nutritional and nonnutritional (immune, endocrine, circulatory)
effects.
Relationship between GH-induced changes
in plasma K+ and [HCO3 ]
Delta HCO3
0,2
0
-2
-1,5
-1
-0,5
0
plasma potassium [mEq/L]
-0,2
-0,4
-0,6
-0,8
-1
-1,2
-1,4
-1,6
-1,8
r=0.597;p<0.015
0,5
1
Relationship between GH-induced changes
in plasma K+ and age
Age [yrs]
30
35
40
45
50
55
60
65
70
75
Changes in plasma K + [mEq/l]
0,2
0
-0,2
r = 0.56 ; p < 0.015
-0,4
-0,6
-0,8
-1
-1,2
-1,4
-1,6
-1,8
Group A
Group B
80
Introduction (3)
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Myostatin, a member of TGF-β family of
signaling molecules (Mc Pherron, Nature 1997)
acts as a negative regulator of skeletal muscle
mass.
Myostatin blockade results in excessive growth
and increased force generation of skeletal muscle
(Tobin 2005)
A role of myostatin in regulation of fiber size and
cell survival has been shown to occur in adult
skeletal muscle (Tobin 2005).
Myostatin is hyperexpressed in AIDS wasting
(Cadavid, 1998)
Relationship between GH-induced changes
in plasma potassium and CRP level
C-reactive protein [mg/l]
0
5
10
15
20
25
30
0,2
0
Changes in plasma potassium [mEq/l]
-0,2
-0,4
-0,6
-0,8
-1
-1,2
-1,4
-1,6
-1,8
r = 0.46 ; p < 0.04
IL-6
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An endocrine cytokine
Major effector of the acute-phase response
Released by fat (adipocytes+macrophages)
accounts for 30% of circulating IL-6
If infused, it causes muscle atrophy, lipolysis and
worsens atherosclerosis (Huber 1999)
Predicts outcome in the elderly (Harris AJM
1999) and in HD patients (Pecoits-Filho NDT
2002, Rao AJKD 2005)
Predicts myocardial infarction in healthy humans
(Ridker, Circulation 2000)
Introduction

Although most of the circulating IL-6 is secreted from
activated mononuclear cells, adipocytes (Mohamed–Alì JCEM
1997) and skeletal muscle (Febbraio MA FASEB 2002) are also a
possible source of this cytokine.

IL-6 mRNA is expressed in resting human muscle and is
rapidly increased by contraction. A release of IL-6 from the
legs (which are mainly composed of skeletal muscle) has been
shown to take place during physical exercise or glycogen
depletion (Febbraio 2004).

In addition, it has been recently observed that insulin increases
IL-6 gene expression in insulin-resistant, but not in healthy
skeletal muscle (Carey 2003). Both reactive oxygen species and
bacterial infections (Lang 2003) can upregulate muscle IL-6,
likely because of an activation of nuclear factor NF kB.
Relationship between GH-induced changes in
plasma K+ and basal Il-6 levels
IL-6 [pg/m l]
0
10
20
30
40
50
60
70
80
90
0,2
Changes in plasma K + [mEq/l]
0
-0,2
-0,4
-0,6
r = 0.54 ; p < 0.03
-0,8
-1
-1,2
-1,4
-1,6
-1,8
Group A
Group B
26
r = 0.395 p < 0.0508
24
22
20
18
IL-6 ALL
16
14
12
10
8
6
4
2
0
-2
2
4
6
8
10
12
14
NP ALL
16
18
20
22
24
5
r = 0.69 p<0.04
2
-4
-7
-10
-13
-16
-19
-22
-25
-28
0
10
20
30
40
50
60
70
IL-6 ART HD
r = -0.2856 p<0.28
0
IL-6 RELEASE CR
IL-6 RELEASE HD
-1
-1
-2
-3
-4
0
5
10
15
20
25
IL-6 ART CFR
30
35
40
45
IL-6 RELEASE by the forearm
Relationship between IL-6 release by the
forearm and arterial IL-6 in CRF patients
r = -0.2856 p=NS
26
21
16
11
6
1
0
5
10
15
20
25
30
-4
Arterial IL-6
35
40
45
IL-6 release by the forearm
Relationship between IL-6 release by the
forearm and arterial IL-6 in HD patients
30
28
26
24
22
20
18
16
14
12
10
8
6
4
2
0
-2
-4 0
r = 0.69 p<0.04
10
20
30
40
50
Arterial IL-6
60
70
IL-6 is produced by human
skeletal muscle
during physical activity
Glycogen depletion
IL-6
Lipolysis
Gluconeogenesis
Arterial interleukin-6 (IL-6) concentration (top), hepatosplanchnic veinarterial (hv-a) IL-6 concentration (middle), and net hepatosplanchnic IL-6
uptake (bottom) before (0 min) and during 120 min of semirecumbent
cycling at 62 ± 2% of maximal oxygen uptake (Febbraio AJP 2003)
IL-6 is released by forearm muscle in
insulin-resistant obese subjects
(Corpeleijn JCEM 2005)
IL-6 exchange
0
-0,5
-1
-1,5
-2
*
-2,5
-3
Ins.Res
Normal
tolerance
Relationships between the percent IL-6 enrichment in the
forearm vein and other variables in CKD patients
Net
Protein
balance
O2
uptake
CO2
release
R2
0.08
p
NS
0.02
NS
0.24
0.04
Efficiency of muscle protein turnover in
patients with CKD (NB/PD)
Recycled Phe
*
50
45
40
35
30
25
20
15
10
5
0
Controls
CRF
CAPD
HD
HD
CRP>10 mg
HD
Malnourished
CRP>10 mg/l