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The ESRD - Inflammation and Malnutrition Axis:
the Data and Conundrum in the Dialysis Setting
Boston 24 April 2009
Peter Stenvinkel, MD, PhD
Peter Stenvinkel, MD, PhD
Chronic Kidney Disease
- Its More Common Than You Think
462.293 individuals from Taiwan.
National prevalence of CKD 11.9%
CKD - a public health priority
Wen et al. Lancet 2008;371:2173-82
Extremely High Risk for Cardiovascular
Complications in CKD
•
AIDS + HAART
>95% five year survival
• ADEMEX
Testicular cancer
95%
•
Breast cancer
85%
Kidney transplant
75%
•
•
4D
HEMO
Bladder cancer
75%
Intensified nutrition
•
Homocysteine
Fellström et al. NEJM 2009Zannad et al. KI 2006
Cano
et al. JASN 2007
Rectal
cancer
62%
lowering AURORA
Sources;
Wanner et al. NEJM 2005
FOSIDIAL
Singh et al.
NEJM
Cervix cancer
60%
Cancer Research
UK
20052006
•
Colonic cancer
54%
•
Dialysis
46%
•
Ovarian cancer
44%
•
Stomach cancer
20% P=0.09
•
Lung cancer
10%
•
Jamieson et al. JAMA 2007
Go et al. NEJM
CHOIR
UK Renal Registry 2006
USRDS 2006
(10 yr survival <15%)
Drueke et al. NEJM 2006
CREATE
Stenvinkel et al. Clin J Am Soc Nephrol 2008;3:505-521
Overflow of Manuscripts on
Systemic Inflammation in CKD
Oh.. please do not put the
mansucript there - that is were I
am going to put my head
At What Point in the Natural History of Chronic
Kidney Disease do Inflammation Become Evident?
8
60
Ducloux et al. 240 PD
N=325
50
Rho=-0.25
Stenvinkel et al. 228 HD
40
GFR (ml/min)
6
CRP (mg/L)
Stenvinkel et al. 304 ESRD
Shlipak et al.
1249 CKD
4
Stenvinkel et al.
53 CKD
P<0.0001
30
20
10
0
,08
,8
8
IL-6 (pg/ml)
2
Sarnak et al.
559 CKD
Tonelli et al.
687 CKD
0
0
10
20
30
GFR (ml/min
40
50
60
Deschamps-Latscha et al. J Immunol 1995
80
800
Causes of Altered Cytokine Balance in CKD
Bennermo et al. Clin Chem Acta 2004
Infection
Dialysis
Ischemia
Injury
+
Response to vaccination
IL-6 -174 genotype and
response to vaccination
Immune system
IL-6 -174 SNP
Increased circulating
Levels of cytokines
Kidney disease
Cholinergic pathway
Muscle
Adipose tissue
Elevated CRP Levels Are a Common
Finding in Patients on Dialysis
Analysis of CRP levels in 1,761 patients on HD
39%
40
Patients (%)
32%
30
n=691
29%
n=566
n=504
20
10
0
CRP <15 mg/L
HD, haemodialysis; CRP, C-reactive protein
CRP 15–<30 mg/L
CRP levels by cohort
Bradbury B et al. 39th Annual Meeting of the American Society of Nephrology;
November 14–19, 2006; San Diego, CA
CRP ≥30 mg/L
CRP - A Moving Target
• 3 month observational study with
weekly hsCRPs
• n=228 prevalent HD-pts
Snaedal et al. In Press AJKD 2009
Less Inflammation in Asian Dialysis Patients
CRP cut-off 8 mg/l
Europe (Stenvinkel et al)
Korea (Noh et al)
0
10
20
30
40
50
60
70
80
90
100
Prevalence (%)
CRP cut-off 10 mg/l
Europe (Stenvinkel et al)
Japan (Iseki et al)
0
10
20
30
40
50
60
70
80
90
100
Prevalence (%)
Europe (Stenvinkel et al)
CRP cut-off 10 mg/l
Hongkong (Wang et al)
0
10
20
30
40
50
60
Prevalence (%)
70
80
90
100
Inflammation Biomarkers Are Risk
Predictors in CKD Patients
Zimmermann et al. KI 1999
Bologa et al. AJKD 1998
IL-6
CRP
N=280
CD14++CD16- monocytes
Heine et al. KI 2008
PTX3
Suliman et al. QJM 2008
Inflammation – A Catalyst for
Other Cardiovascular Risk Factors? (I)
100
Matsubara et al. In Press JN 2009
100
Metry et al. EJCI 2008
Low OPG
OPGand
andlow
lowCRP
CRP
high FetuinCarrero
and lowetCRP
al. JASN 2009
60
100
80
40
20
0
0
High
OPG
and
lowCRP
CRP
low
OPG
and
low
low Fetuin and low CRP
LowOPG
OPGand
andhigh
high CRP
CRPLow IL-6 andCarrero
high testosterone
high
et al. CJASN 2008
h igh C80R P
60
high Fetuin and high CRP
low
OPG
High
OPGand
andhigh
highCRP
CRPHigh IL-6 and high testosterone
Patient survival
Patients survival
Patients survival
80
40
20
12
24
0
0
6
60
low Fetuin and high CRP
40
36
48
60
20
Months Low IL-6 and low testosterone
12 not shown
18 due to24
30
few patients
0
0
10
20
Months
High IL-6 and low testosterone
36
30
Months
42
40
50
Exaggerated
mortality risk
Exacerbation of
protein-energy
wasting and
vascular
calcification
Self-enhancement
of the
inflammatory
cascade
The inflammation-catalyst hypothesis:
Persistent inflammation may exacerbate the
effect of other concurrent risk factors. The
presence of persistent inflammation magnifies
the risk of poor outcome via mechanisms
related to self-enhancement of the
inflammatory cascade and exacerbation of
wasting and vascular calcification processes.
Inflammation – A Catalyst for
Other Cardiovascular Risk Factors? (II)
52 non-diabetic CAPD patients
CCA-IMT measured
at baseline and after
36 months
Cardiovascular events
Kidney Int Sept 2008
94 HD-pts
followed
35 months
Kim, D. K. et al. NDT 2008 23:1011-1018
Girndt et al. Kidney Int 2008;73:622-9
Chemokines and Their Receptor CCR5 Play a
Role in the Pathogenesis of Atherosclerosis
Blockade of the CCR5 may provide a novel therapeutic
approach in inflamed dialysis patients.
Incident dialysis patients
• NECOSAD (n=413)
• MIA (n=302)
It is suggested that all the Delta CCR5 alleles originated from a single mutation event that
occurred 1000 yrs BC and that subsequent epidemics of plague (or smallpox) put a selective
pressure on the CCR5 gene.
Inflamed pts carrying
Patients with a dysfunctional
CCR5 due to the gene
polymorphism CCR5 deletion
32 (CCR5∆32) have improved
prognosis in atherosclerotic
disease (Szalai et al.
Atherosclerosis 2001)
the deletion allele
Inflamed pts carrying
the wild type genotype
Muntinghe et al.In Press JASN 2009
Multiple Causes of Wasting Beside Malnutrition
Renal disease per se
Malnutrition
Co-morbidity
Fouque et al. KI 2008
Residual renal function
Protein intake
Congestive heart failure
Uremic toxins
Energy intake
Vascular disease
Endocrine abnormalities
Vitamin intake
Diabetes mellitus
Amino acid abnormalities
Depression
Acidosis
Other comorbidity
Dialysis procedure
Inflammation
Dialysate endotoxins
Graft and fistula infections
Infections
Other factors
Oxidative stress
Dialysis adequacy
Drugs
Accumulation of AGEs
Bioincompatibility
Social factors
Genetic factors
Nutrient losses (dialysate)
Protein assimilation
Inflammation and Wasting have Additive
Effects on Cardiovascular Death
Surviving (%)
100
Data adjusted for age, gender and diabetes mellitus
No wasting + no
inflammation; n=160
80
No wasting +
inflammation; n=45
Wasting + no
inflammation; n=50
60
Wasting +
inflammation; n=55
N=310
Likelihood ratio 34,5
P<0.0001
40
0
12
24
36
48
Observation time (months)
60
Avesani et al. Kidney Int 2007
NDT 2008
815 incident dialysis pts followed 7 yrs
Expected death rates
Suggest the existence of a syndrome where the whole is
more than its parts
45
14
7
None
PEW
18
21 18
27 25
24 22
29
11
Inflam
CVD
PEW +
Inflam
PEW +
CVD
Inflam +
CVD
Inflam +
CVD + PEW
CRP: Is it a risk factor or
just a a risk marker?
CJASN 2008
Lancet 2005
Common haplotypes for the CRP region
Estimated frequency (SE)
Plasma CRP (mg/L)
(geometric mean, 95%CI)
• Raised CRP is linked to metabolic syndrome and
CGC
1.81 (1.66-1.96)
cardiovascular
risk. 0.37 (0.006)
•CGT
However, associations
between CRP and1.70health
outcomes
0.26 (0.005)
(1.58-1.83)
might be affected by reverse causation or confounding.
CAC
0.30 (0.006)
• Up-regulation of cytokines
as a result of obesity2.03
or(1.90-2.18)
kidney disease.
• Environmental factors,0.07
such
as smoking and socioeconomic
positions.
1.39 (1.23-1.56)
(0.003)
GGT
• To generate unconfounded and unbiased estimates of any
causal association between CRP and the metabolic syndrome.
• CRP haplotypes not associated with potential confounding
variables.
2008
CJASN 2008
IL-6 Predicts Poor Outcome in ESRD
Bologa et al. AJKD 1998
NDT 2002
NDT 2004
AJKD 2005
Pro-atherogenic Effects of IL-6
High IL-6 reflects endothelial
dysfunction (Nawawi et al.
IL-6 exacerbates early
atherosclerosis in mice
Atherosclerosis 2003)
(Huber et al Arterioscler Thromb
Vasc Biol 1999)
IL-6
IL-6 decrease adiponectin
mRNA (Bruun et al Am J
IL-6 expression is involved at
the fibrous plaque stage
Physiol Endocrinol Metab 2003)
(Elhage et al. Atherosclerosis
2001).
Chlamydia pneumoniae IgA
and elevated level of IL-6 may
synergize to accelerate
coronary artery disease.(Jha
Polymorphism in the IL-6
promoter region is associated
with markers of subclinical
atherosclerosis (Hulkonnen et al.
et al. J Cardiol 2008)
Atherosclerosis 2008)
Catabolic Effects of IL-6
Stimulates breakdown of
muscle protein (Cederholm
Promotes cancer cachexia
(Argiles et al. Curr Opin Clin Nutr
Metab Care 2003)
et al AJCN 1999)
IL-6 infusion reduces
food intake and gastric
emptying (McCarthy Res
Nurs Health 2000)
IL-6 receptor antibody
inhibit muscle atrophy in
IL-6 transgenic mice
(Tsujinaka T et al. JCI 1996)
Activation ofIL-6
the
acute phase
response by IL-6
requires high rates
of hepatic protein
synthesis
IL-6 down-regulate
albumin mRNA and inhibit
albumin synthesis (Andus et
al. Eur J Immunol 1988).
IL-6 inhibits the secretion
of IGF-1 (Barbieri et al. Am J
Physiol Endocriln2003)
Variants in the IL-6 Gene is Associated with
Vascular Disease and Metabolic Syndrome
Diabetes 2000
Diabetes 2004
JASN 2006
Multiple Inflammatory Pathways
Contribute to the Development of CVD
“Lymphotoxin- and IL-6 gene variants
independently predicted risk for CVD
among dialysis patients”.
Can Barack Obama Help Nephrology?
Obama to broaden genetics role in medical care
'Personalized medicine' expected to get boost
with incoming administration
By RICARDO ALONSO-ZALDIVARupdated 5:15 p.m. ET Nov. 28, 2008 WASHINGTON
For years, scientists have held out hope that the rapidly evolving field of
genetics could transform medical diagnosis and treatment, moving
beyond a trial-and-error approach. But the vision of individualized
treatment based on a patient's genetic makeup and other biological
markers has yet to materialize, even if better use of genetic information
has led to advances in cancer care and other areas. Now the pursuit of
"personalized medicine" is expected to get a major push from the
incoming administration of President-elect Barack Obama. As a
senator, Obama introduced legislation to coordinate the sometimes
conflicting policies of government agencies and provide more support
for private research. He remains keen on the idea.
Classical Pro-inflammatory Cytokines are
not the Sole Mediators of Muscle Loss
TWEAK
Many studies
show
that
TWEAK
induces
skeletal
neutralization
ofthrough
one or
muscle
atrophy
more of the
classical
inhibition
of the
ubiquitincytokines does
lead
proteasome
andnot
NF-kB
to amelioration of muscle
systems
atrophy.
Newly described member of the TNF
superfamily which induce
• cellular growth and proliferation
• angiogenesis
• osteoclastogenesis
• stimulation of apoptosis
FASEB 2007
Levels of TWEAK Modulate the Effects of Inflammation
on Outcome in Prevalent Dialysis Patients
P<0.05
400
350
Low P<0.05
IL-6, high sTWEAK
Patients survival
IGF-1, ng/mL
P<0.05
300
Low IL-6, low sTWEAK
250
High IL-6, low sTWEAK
200
150
be associated with
cardiovascular and all-cause
mortality in HD patients with
systemic inflammation
through pathways that may
relate to increased muscle
wasting.
• TWEAK may be a major
mediator of skeletal
Months muscle
loss in inflamed disease states.
Low IL-6, low sTWEAK
Low IL-6, high sTWEAK
High IL-6, low sTWEAK
High IL-6, high sTWEAK
High IL-6, high sTWEAK
100
50
Adjusted Mortality
• sTWEAK
plasma levels may
Patients survival
Crude mortality
Log rank
p<0.0001
Low
0[χ2]: 27.2, High
1
TWEAK
TWEAK
Low IL-6
Months
Low
2
TWEAK
High
3
TWEAK
High IL-6
Likelihood Ratio [χ2]: 79.13, p<0.0001
Carrero et al. CJASN 2008
CJASN 2008
Pentraxin 3 - a New Kid on the Block
Toll-like receptor
Interleukin-6
TNF-a
IL-1
Mononuclear cells
Fibroblasts
Endothelial cells
Adipocytes (?)
Short pentraxins
• CRP
• SAP
Opsonization
Inflammation tuning
Long pentraxins
• PTX3
Complement activation
Resistance to pathogens
1.00
CJASN 2007
75,0
50,0
0.75
IL-6
25,0
0.50
0.75
Pentraxin-3, ng/ml
7,5
5,0
2,5
0.25
0.50
CRP
PTX-3
0,8
0,5
0.25
0.00
Sensitivity
Sensitivity
1.00
0,3
Rho=-0.54, p<0.0001
0.00
0,8
0.00
2,5
0 .25
5,0
25,0
7,5
0. 50
GFR,1-ml/min
Specifici ty
50,0
0.75
75,0
1.0 0
Correlations Between PTX3, Urinary Albumin
Excretion and Endothelial Function
Type-2 DM with albuminuria
but normal renal function
U-Albumin, mg/24 hours
5000
500
Suliman et al. Submitted 2007
50
CKD 5 patients
5
0,8
CJASN 2008
2,0
4,0
6,0
Rho=0.22; p=0.002
8,0
PTX3, ng/ml
20,0
40,0
60,0
12 Weeks of ACEI Treatment (Ramipril)
Normalizes Endothelial Dysfunction and PTX3
• 49 selected typ-2 diabetic patients with
GFR ≥90 ml/min and urinary protein
excretion 500-3000 mg/day.
• Open label study The study was registered in
clinicaltrials.gov as NCT00674596
delta PTX3 (%)
0,00
-20,00
-40,00
-60,00
-80,00
R Sq Linear = 0,336
-100,00
-20,00
0,00
20,00
40,00
60,00
delta flow-mediated dilatation (%)
Yilmaz et al. CJASN 2009
Which Way To Go Regarding Treatment?
Integrated Treatment Approach of
Inflammatory-Associated Wasting
Stenvinkel et al. Semin Dial Nov 2004
Targeted
anti-cytokine
therapy
Dietary and pharmacological
anti-inflammatory and anti-oxidative
treatment
Correction of acidosis, anemia,
vitamin supplementation
Adequate energy and protein intake
Adequate dialysis treatment
How Do We Handle Dialysis Patients with Signs
of Inflammation?
Percentage of patients with a normal CRP level at baseline and at 12-mo follow-up
Evaluate and treat
co-morbidities that
may cause
inflammation
Evaluate and treat
potential dialysis
related causes of
inflammation
Consider antiinflammatory
treatment
strategies
• Infectious complications
• Unpure dialysate
• Nutritional intervention
• Silent ischemic heart disease
• Infectious complications of
• Physical training
haemodialysis access
Panichi, V. et al. Nephrol. Dial. Transplant. 2008 23:2337-2343
• Intercurrent clinical events
Short daily HDal
Conventional HDal
• Peridontal disease
• Thrombosed fistula or graft
• Failed kidney transplant
• Bioincompatible
membranes
Ayus, J. C. et al. JASN
2005;16:2778-88
• Volume overload
• Bioincompatible dialysis fluids
• Inflammatory diseases
• Peritonitis
• Hemodiafiltration
• Pharmacological
intervention
Novel Approaches to the Treatment of
Inflammation-Related Wasting in Dialysis
• act via endorphin receptors
Cytokine
Enhancing
• inhibiting prostaglandin
synthesis
releasing
cell
synthesis
• inhibiting cytokine production
Blocking
synthesis
Strasser et al. J Clin Oncol 2006
Anticachectic
cytokines
(IL-10, IL-15)
Procachectic
cytokines
(IL-6, TNF)
Favouring
action
JASN 2007
Blocking
action
R
R
Lancet 2003
Intracellular signaling
pathway
Protein
Target cell
Argilés et al. Drug Discovery Jan 2008
AA
NEJM 1978
Hypothesis: Persistent
inflammation in uremia may
affect drug metabolism.
A man should never
speak longer in public
than he can make love
in private
What Did He Say?
 Inflammation biomarkers consistently predicts poor outcome
in dialysis patients.
 Recent evidence suggest that inflammation serve as a
catalyst for other risk factors and magnify the risk of poor
outcome via exacerbation of both wasting and vascular
processes.
 Evidence suggest that whereas the short pentraxin CRP is
not causal in the pathology of vascular disease IL-6 is.
 In CKD the long pentraxin PTX3 is linked to endothelial
dysfunction and urinary albumin excretion.
 CKD is characterized by a loss of phenotypic plasticity - the
uremic phenotype may be much more susceptible to
underlying genetic variants.
“Art is I - Science is We”
Claude Bernard
Welcome to the ISBP 2009 Stockholm
Date: 17-19 Sept 2009