Peter Stenvinkel, MD, PhD

Peter Stenvinkel, MD, PhD

Inflammation in End-stage Renal Disease - the fire that burns within

Antalya 14 May 2009

Wen et al. Lancet 2008;371:2173-82

462.293 individuals from Taiwan.National prevalence of CKD 11.9%

Chronic Kidney Disease - Its More Common Than You Think

CKD - a public health priority

G Papandreo, Greece Y Andropov, Soviet Union VP Singh, India Kim Il Jong, North Korea

B Kreisky, Austria D Lange, New Zeeland F Marcos, Phillipines Osama Bin Laden, Residence unknown

Rumour

Rumour

Extremely High Risk for Cardiovascular Complications in CKD

Go et al. NEJM

• AIDS + HAART >95% five year survival• Testicular cancer 95%• Breast cancer 85%• Bladder cancer 75%• Kidney transplant 75%• Rectal cancer 62%• Cervix cancer 60%• Colonic cancer 54%• Dialysis 46% (10 yr survival <15%)

• Ovarian cancer 44%• Stomach cancer 20%• Lung cancer 10%

Sources;Cancer Research UK 2005UK Renal Registry 2006USRDS 2006

ADEMEX

HEMO

Cano et al. JASN 2007

Intensified nutritionHomocysteinelowering

Jamieson et al. JAMA 2007

Wanner et al. NEJM 2005

4D

Fellström et al. NEJM 2009

AURORA FOSIDIAL

P=0.09

Zannad et al. KI 2006

CHOIRSingh et al. NEJM 2006

Drueke et al. NEJM 2006

CREATE

Stenvinkel et al. Clin J Am Soc Nephrol 2008;3:505-521

Oh.. please do not put the manuscript there - that is were I am going to put my head

Overflow of Manuscripts on Systemic Inflammation in CKD

At What Point in the Natural History of Chronic Kidney Disease do Inflammation Become Evident?

0

2

4

6

8

CR

P (m

g/L)

0 10 20 30 40 50 60

GFR (ml/min

Ducloux et al. 240 PD

Stenvinkel et al. 228 HD

Stenvinkel et al. 304 ESRD

Sarnak et al. 559 CKD

Stenvinkel et al. 53 CKD

Shlipak et al. 1249 CKD

Tonelli et al. 687 CKD

0

10

20

30

40

50

60

GFR (ml/min)

,08 ,8 8 80 800

IL-6 (pg/ml)

N=325

Rho=-0.25

P<0.0001

Deschamps-Latscha et al. J Immunol 1995

Causes of Altered Cytokine Balance in CKD

Kidney disease

Muscle Adipose tissue

InfectionDialysisIschemiaInjury

Immune system

Cholinergic pathway

Increased circulatingLevels of cytokines

Bennermo et al. Clin Chem Acta 2004

Response to vaccination

IL-6 -174 SNP

IL-6 -174 genotype and response to vaccination

+

Genetics

Elevated CRP Levels Are a Common Finding in Patients on Dialysis

Bradbury B et al. 39th Annual Meeting of the American Society of Nephrology; November 14–19, 2006; San Diego, CA

CRP <15 mg/L

CRP levels by cohort

Analysis of CRP levels in 1,761 patients on HD

Patie

nts

(%) n=566

n=691

n=504

0

10

40

20

3032%

39%

29%

CRP 15–<30 mg/L CRP ≥30 mg/L

HD, haemodialysis; CRP, C-reactive protein

CRP - A Moving Target

Snaedal et al. In Press AJKD 2009

• 3 month observational study with weekly hsCRPs• n=228 prevalent HD-pts

Hazard ratios for death following adjustment for age, sex,

vintage, co-morbidity (Davis score) and type of access

Less Inflammation in Asian Dialysis Patients

0 10 20 30 40 50 60 70 80 90 100

Prevalence (%)

Korea (Noh et al)

Europe (Stenvinkel et al) CRP cut-off 8 mg/l

0 10 20 30 40 50 60 70 80 90 100

Prevalence (%)

Hongkong (Wang et al)

Europe (Stenvinkel et al) CRP cut-off 10 mg/l

Prevalence (%) 0 10 20 30 40 50 60 70 80 90 100

Japan (Iseki et al)

Europe (Stenvinkel et al) CRP cut-off 10 mg/l

Inflammation Biomarkers Are Risk Predictors in CKD Patients

Zimmermann et al. KI 1999

N=280CRP

Bologa et al. AJKD 1998

IL-6

Suliman et al. QJM 2008PTX3

Heine et al. KI 2008

CD14++CD16- monocytes

KI Sept 2008

Inflammation – A Catalyst for Other Cardiovascular Risk Factors? (I)

0 12 24 36 48 600

20

40

60

80

100

OPG and low CRP

low OPG and low CRP

high OPG and high CRP

low OPG and high CRP

Months

Patie

nts s

urvi

val

Matsubara et al. In Press JN 2009

Low OPG and low CRP

High OPG and low CRP

Low OPG and high CRP

High OPG and high CRP

0 6 12 18 24 30 36 420

20

40

60

80

100

high Fetuin and low CRP

low Fetuin and low CRP

high Fetuin and high CRP

low Fetuin and high CRP

Months

Patie

nts s

urvi

val

Metry et al. EJCI 2008

high CRP

0

20

40

60

80

100Pa

tient

surv

ival

0 10 20 30 40 50

Months

Low IL-6 and high testosterone

High IL-6 and high testosterone

High IL-6 and low testosterone

Low IL-6 and low testosteronenot shown due to few patients

Carrero et al. JASN 2009

Carrero et al. CJASN 2008

Self‐enhancement of the inflammatory 

cascade

Exacerbation of protein‐energy wasting and vascular 

calcification

Exaggerated mortality risk

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

Kim, D. K. et al. NDT 2008 23:1011-1018

Kidney Int Sept 2008

94 HD-ptsfollowed 35 months

Girndt et al. Kidney Int 2008;73:622-9

Cardiovascular events

The distinct subset of CD14++ CD16+

monocytes is characterized by their unique

pattern of chemokine receptors.

Chemokines and Their Receptor CCR5 Play a Role in the Pathogenesis of Atherosclerosis

Patients with a dysfunctionalCCR5 due to the gene polymorphism CCR5 deletion 32 (CCR5∆32) have improved prognosis in atherosclerotic disease (Szalai et al. Atherosclerosis 2001)

Blockade of the CCR5 may provide a novel therapeutic approach in inflamed dialysis patients.

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.

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.

Incident dialysis patients• NECOSAD (n=413)• MIA (n=302)

Muntinghe et al.In Press JASN 2009

Inflamed pts carrying

the deletion allele

Inflamed pts carrying the wild type genotype

Residual renal function

Uremic toxins

Endocrine abnormalities

Amino acid abnormalities

Acidosis

Residual renal function

Uremic toxins

Endocrine abnormalities

Amino acid abnormalities

Acidosis

Renal disease per se

Dialysate endotoxins

Graft and fistula infections

Dialysis adequacy

Bioincompatibility

Nutrient losses (dialysate)

Dialysate endotoxins

Graft and fistula infections

Dialysis adequacy

Bioincompatibility

Nutrient losses (dialysate)

Dialysis procedure

Congestive heart failure

Vascular disease

Diabetes mellitus

Depression

Other comorbidity

Congestive heart failure

Vascular disease

Diabetes mellitus

Depression

Other comorbidity

Co-morbidity

Protein intake

Energy intake

Vitamin intake

Protein intake

Energy intake

Vitamin intake

Malnutrition

DrugsSocial factorsProtein assimilation

Multiple Causes of Wasting Beside Malnutrition

DrugsSocial factorsProtein assimilation

Other factors

Infections

Oxidative stress

Accumulation of AGEs

Genetic factors

Infections

Oxidative stress

Accumulation of AGEs

Genetic factors

Inflammation

Fouque et al. KI 2008

Inflammation and Wasting have Additive Effects on Cardiovascular Death

0 12 24 36 48 6040

60

80

100 Data adjusted for age, gender and diabetes mellitus

Wasting + inflammation; n=55

Wasting + no inflammation; n=50

No wasting + no inflammation; n=160

No wasting + inflammation; n=45

Sur

vivi

ng (%

)

Observation time (months)

N=310Likelihood ratio 34,5P<0.0001

Avesani et al. Kidney Int 2007

714 11

18 2127 24

1825 22

29

45

None PEW Inflam CVD PEW +Inflam

PEW +CVD

Inflam +CVD

Inflam +CVD + PEW

Mor

talit

y ra

tes

(100

per

son

year

s) 815 incident dialysis pts followed 7 yrsExpected death rates

Suggest the existence of a syndrome where the whole is more than its parts

NDT 2008

CJASN 2008

CRP: Is it a risk factor orjust a a risk marker?

Lancet 2005

• Raised CRP is linked to metabolic syndrome and cardiovascular risk.• However, associations between CRP and health outcomes might be affected by reverse causation or confounding.

• Up-regulation of cytokines as a result of obesity or kidney disease.• Environmental factors, such as smoking and socioeconomic positions.1.39 (1.23-1.56)0.07 (0.003)GGT

Plasma CRP (mg/L) (geometric mean, 95%CI)

Estimated frequency (SE)

2.03 (1.90-2.18)0.30 (0.006)CAC

1.70 (1.58-1.83)0.26 (0.005)CGT

1.81 (1.66-1.96)0.37 (0.006)CGC

Common haplotypes for the CRP region

• To generate unconfounded and unbiased estimates of any causal association between CRP and the metabolic syndrome.

• CRP haplotypes not associated with potential confounding variables.

Conclusion: CRP is a risk marker not a risk factor.

Inflammation may rather play a causal role in

vascular disease via upstream effectors.

2008

CJASN 2008

IL-6 Predicts Poor Outcome in ESRD

AJKD 2005

NDT 2004

NDT 2002Bologa et al. AJKD 1998

Pro-atherogenic Effects of IL-6

IL-6 exacerbates early atherosclerosis in mice(Huber et al Arterioscler Thromb Vasc Biol 1999)

Polymorphism in the IL-6 promoter region is associated with markers of subclinical atherosclerosis (Hulkonnen et al. Atherosclerosis 2008)

High IL-6 reflects endothelial dysfunction (Nawawi et al. Atherosclerosis 2003)

Chlamydia pneumoniae IgA and elevated level of IL-6 may synergize to accelerate coronary artery disease.(Jha et al. J Cardiol 2008)

IL-6

IL-6 decrease adiponectin mRNA (Bruun et al Am J Physiol Endocrinol Metab 2003)

IL-6 expression is involved at the fibrous plaque stage(Elhage et al. Atherosclerosis 2001).

Catabolic Effects of IL-6

Stimulates breakdown of muscle protein (Cederholm et al AJCN 1999)

IL-6 inhibits the secretion of IGF-1 (Barbieri et al. Am J Physiol Endocriln2003)

Promotes cancer cachexia (Argiles et al. Curr Opin Clin Nutr Metab Care 2003)

IL-6 receptor antibody inhibit muscle atrophy in IL-6 transgenic mice(Tsujinaka T et al. JCI 1996)

IL-6

IL-6 infusion reduces food intake and gastric emptying (McCarthy Res Nurs Health 2000)

IL-6 down-regulate albumin mRNA and inhibit albumin synthesis (Andus et al. Eur J Immunol 1988).

Activation of the acute phase response by IL-6 requires high rates of hepatic protein synthesis

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-α and IL-6 gene variants independently predicted risk for CVD among dialysis patients”.

Could the development of gene chips

help us to identify ris

k patients?

Classical Pro-inflammatory Cytokines are not the Sole Mediators of Muscle Loss

Many studies show that neutralization of one or more of the classical cytokines does not lead to amelioration of muscle atrophy.

Many studies show that neutralization of one or more of the classical cytokines does not lead to amelioration of muscle atrophy.

Newly described member of the TNF superfamily which induce

• cellular growth and proliferation

• angiogenesis

• osteoclastogenesis

• stimulation of apoptosis

Newly described member of the TNF superfamily which induce

• cellular growth and proliferation

• angiogenesis

• osteoclastogenesis

• stimulation of apoptosis

TWEAK

FASEB 2007

TWEAK induces skeletal muscle atrophy through inhibition of the ubiquitin-proteasome and NF-κB systems

TWEAK induces skeletal muscle atrophy through inhibition of the ubiquitin-proteasome and NF-κB systems

Low IL‐6, low sTWEAK

Low IL‐6, high sTWEAK

High IL‐6, low sTWEAK

High IL‐6, high sTWEAK

Log rank [χ2]: 27.2, p<0.0001 

Months

Patien

ts survival

Crude mortality

Low IL‐6, low sTWEAK

Low IL‐6, high sTWEAK

High IL‐6, low sTWEAK

High IL‐6, high sTWEAK

Months

Likelihood Ratio [χ2]: 79.13, p<0.0001 

Adjusted Mortality

Patien

ts survival

50

100

150

200

250

300

350

400

0 1 2 3

IGF-

1, n

g/m

L

Low TWEAK

Low TWEAK

High TWEAK

High TWEAK

Low IL-6 High IL-6

P<0.05

P<0.05

P<0.05

Carrero et al. CJASN 2008

Levels of TWEAK Modulate the Effects of Inflammation on Outcome in Prevalent Dialysis Patients

• sTWEAK plasma levels may 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 muscle loss in inflamed disease states.

CJASN 2008

Pentraxin 3 - a New Kid on the Block

Short pentraxins• CRP• SAP

Interleukin-6

Long pentraxins• PTX3

Mononuclear cellsFibroblasts Endothelial cellsAdipocytes (?)

Toll-like receptor

TNF-a

IL-1β

Opsonization Inflammation tuning Complement activation Resistance to pathogens

0,8 2,5 5,0 7,5 25,0 50,0 75,0

0,3

0,5

0,8

2,5

5,0

7,5

25,0

50,0

75,0

GFR, ml/min

Pent

raxi

n-3,

ng/

ml

Rho=-0.54, p<0.0001

0.00

0.25

0.50

0.75

1.00

Sen

sitiv

ity

0.00 0 .25 0

PTX-3

IL-6

CRP

0.00

0.25

0.50

0.75

1.00

Sens

itivi

ty

. 50 0.75 1.0 01- Specifici ty

CJASN 2007

Correlations Between PTX3, Urinary Albumin Excretion and Endothelial Function

Type-2 DM with albuminuriabut normal renal function

Suliman et al. Submitted 2007

0,8 2,0 4,0 6,0 8,0 20,0 40,0 60,05

50

500

5000

PTX3, ng/ml

U-A

lbum

in, m

g/24

hou

rs

Rho=0.22; p=0.002

CKD 5 patients

CJASN 2008

12 Weeks of ACEI Treatment (Ramipril) Normalizes Endothelial Dysfunction and PTX3

60,0040,0020,000,00-20,00

delta PTX3 (%)

0,00

-20,00

-40,00

-60,00

-80,00

-100,00

R Sq Linear = 0,336

delta flow-mediated dilatation (%)

• 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

Yilmaz et al. CJASN 2009

Which Way To Go Regarding Treatment?

There will never be a silver bullet

Correction of acidosis, anemia, vitamin supplementation

Adequate energy and protein intake

Adequate dialysis treatment

Integrated Treatment Approach of Inflammatory-Associated Wasting

Targetedanti-cytokine

therapy

Dietary and pharmacological anti-inflammatory and anti-oxidative

treatment

Stenvinkel et al. Semin Dial Nov 2004

How Do We Handle Dialysis Patients with Signs of Inflammation?

Evaluate and treat co-morbidities that

may cause inflammation

• Infectious complications• Silent ischemic heart disease• Intercurrent clinical events• Peridontal disease• Failed kidney transplant• Volume overload• Inflammatory diseases

Consider anti-inflammatory

treatment strategies

• Nutritional intervention• Physical training• Pharmacological intervention

Evaluate and treat potential dialysis related causes of

inflammation

• Unpure dialysate• Infectious complications of haemodialysis access

• Thrombosed fistula or graft• Bioincompatible membranes• Bioincompatible dialysis fluids• Peritonitis• Hemodiafiltration

Panichi, V. et al. Nephrol. Dial. Transplant. 2008 23:2337-2343

Ayus, J. C. et al. JASN 2005;16:2778-88

Percentage of patients with a normal CRP level at baseline and at 12-mo follow-up

Conventional HDalShort daily HDal

Novel Approaches to the Treatment of Inflammation-Related Wasting in Dialysis

Argilés et al. Drug Discovery Jan 2008

• act via endorphin receptors• inhibiting prostaglandin synthesis• inhibiting cytokine production

Strasser et al. J Clin Oncol 2006

JASN 2007

Lancet 2003

Anticachectic cytokines

(IL-10, IL-15)

Procachectic cytokines

(IL-6, TNF)

Cytokine releasing cell

R

R

Intracellular signalingpathway

Protein AA

Target cell

Enhancing synthesis

Blockingsynthesis

Favouring action

Blocking action

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.

Welcome to the ISBP 2009 Stockholm Date: 17-19 Sept 2009

Claude Bernard

“Art is I - Science is We”