Inflammation in End-stage Renal Disease - the fire that burns within. Peter Stenvinkel, MD, PhD

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1 Inflammation in End-stage Renal Disease - the fire that burns within Antalya 14 May 2009 Peter Stenvinkel, MD, PhD Peter Stenvinkel, MD, PhD

2 Chronic Kidney Disease - Its More Common Than You Think individuals from Taiwan. National prevalence of CKD 11.9% CKD - a public health priority Wen et al. Lancet 2008;371:

3 Rumour 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

4 Extremely High Risk for Cardiovascular Complications in CKD AIDS + HAART >95% five year survival ADEMEX Testicular cancer 95% Breast cancer 85% Bladder HEMO 4D cancer 75% Intensified nutrition Kidney transplant 75% Homocysteine Rectal Cano cancer et al. JASN 2007 lowering 62% Cervix cancer 60% Colonic cancer 54% Dialysis 46% (10 yr survival <15%) Ovarian cancer 44% Stomach cancer 20% Lung cancer 10% Fellström et al. NEJM 2009Zannad et al. KI 2006 AURORA Wanner et al. NEJM 2005 Sources; FOSIDIAL Cancer Research Singh et al. UK NEJM Jamieson et al. JAMA 2007 CHOIR UK Renal Registry 2006 USRDS 2006 Drueke et al. NEJM 2006 P=0.09 CREATE Go et al. NEJM

5 Stenvinkel et al. Clin J Am Soc Nephrol 2008;3:

6 Overflow of Manuscripts on Systemic Inflammation in CKD Oh.. please do not put the manuscript there - that is were I am going to put my head

7 At What Point in the Natural History of Chronic Kidney Disease do Inflammation Become Evident? CRP (mg/l) Ducloux et al. 240 PD Stenvinkel et al. 228 HD Stenvinkel et al. 304 ESRD Stenvinkel et al. 53 CKD Shlipak et al CKD GFR (ml/min) N=325 Rho=-0.25 P<0.0001,08, IL-6 (pg/ml) 2 Sarnak et al. 559 CKD Tonelli et al. 687 CKD GFR (ml/min Deschamps-Latscha et al. J Immunol 1995

8 Causes of Altered Cytokine Balance in CKD Infection Dialysis Ischemia Injury + Bennermo et al. Clin Chem Acta 2004 Response to vaccination IL genotype and response to vaccination Genetics Immune system IL SNP Increased circulating Levels of cytokines Kidney disease Cholinergic pathway Muscle Adipose tissue

9 Elevated CRP Levels Are a Common Finding in Patients on Dialysis Analysis of CRP levels in 1,761 patients on HD Patients (%) % n=566 39% n=691 29% n=504 0 CRP <15 mg/l CRP 15 <30 mg/l CRP 30 mg/l HD, haemodialysis; CRP, C-reactive protein CRP levels by cohort Bradbury B et al. 39 th Annual Meeting of the American Society of Nephrology; November 14 19, 2006; San Diego, CA

10 CRP - A Moving Target Hazard ratios for death following adjustment for age, sex, vintage, co-morbidity (Davis score) and type of access 3 month observational study with weekly hscrps n=228 prevalent HD-pts Snaedal et al. In Press AJKD 2009

11 Less Inflammation in Asian Dialysis Patients Europe (Stenvinkel et al) CRP cut-off 8 mg/l Korea (Noh et al) Prevalence (%) Europe (Stenvinkel et al) CRP cut-off 10 mg/l Japan (Iseki et al) Prevalence (%) Europe (Stenvinkel et al) CRP cut-off 10 mg/l Hongkong (Wang et al) Prevalence (%)

12 Inflammation Biomarkers Are Risk Predictors in CKD Patients Bologa et al. AJKD 1998 Zimmermann et al. KI 1999 IL-6 CRP N=280 KI Sept 2008 CD14++CD16- monocytes Heine et al. KI 2008 PTX3 Suliman et al. QJM 2008

13 Inflammation A Catalyst for Other Cardiovascular Risk Factors? (I) 100 Matsubara et al. In Press JN 2009 Patients survival Patients survival Metry et al. EJCI 2008 Low OPG and low lowcrp high FetuinCarrero and lowet CRP al. JASN low High OPG OPG and and low low CRP CRP low Fetuin and low CRP high Low OPG OPG and and high high CRP CRPLow IL-6 and Carrero high testosterone et al. CJASN 2008 high CRP 80 high Fetuin and high CRP low High OPG OPG and and high high CRP CRPHigh IL-6 and high testosterone 60 Patient survival low Fetuin and high CRP 20 High IL-6 and low testosterone 0 Months Low IL-6 and low testosterone not shown 18 due to 24 few patients Months Months

14 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.

15 Inflammation A Catalyst for Other Cardiovascular Risk Factors? (II) Cardiovascular events 52 non-diabetic CAPD patients CCA-IMT measured at baseline and after 36 months Kidney Int Sept HD-pts followed 35 months The distinct subset of CD14 ++ CD16 + monocytes is characterized by their unique pattern of chemokine receptors. Kim, D. K. et al. NDT : Girndt et al. Kidney Int 2008;73:622-9

16 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. It It is is suggested suggested that that all all the the Delta Delta CCR5 CCR5 alleles alleles originated originated from from a a single single mutation mutation event event that that occurred occurred yrs yrs BC BC and and that that subsequent subsequent epidemics epidemics of of plague plague (or (or smallpox) smallpox) put put a a selective selective pressure pressure on on the the CCR5 CCR5 gene. 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) Muntinghe et al.in Press JASN 2009 Inflamed pts carrying the wild type genotype Incident dialysis patients NECOSAD (n=413) MIA (n=302) the deletion allele

17 Multiple Causes of Wasting Beside Malnutrition Renal disease per se Residual renal renal function function Uremic Uremic toxins toxins Endocrine abnormalities Amino Amino acid acid abnormalities Acidosis Malnutrition Protein Protein intake intake Energy Energy intake intake Vitamin Vitamin intake intake Co-morbidity Fouque et al. KI 2008 Congestive heart heart failure failure Vascular disease disease Diabetes mellitus mellitus Depression Other Other comorbidity Dialysis procedure Dialysate endotoxins Graft Graft and and fistula fistula infections Dialysis Dialysis adequacy Bioincompatibility Nutrient Nutrient losses losses (dialysate) Other factors Drugs Drugs Social Social factors factors Protein Protein assimilation Inflammation Infections Oxidative stress stress Accumulation of of AGEs AGEs Genetic Genetic factors factors

18 Inflammation and Wasting have Additive Effects on Cardiovascular Death 100 Data adjusted for age, gender and diabetes mellitus Surviving (%) N=310 Likelihood ratio 34,5 P< Observation time (months) No wasting + no inflammation; n=160 No wasting + inflammation; n=45 Wasting + no inflammation; n=50 Wasting + inflammation; n=55 Avesani et al. Kidney Int 2007

19 NDT 2008 Mortality rates (100 person years) 815 incident dialysis pts followed 7 yrs Expected death rates Suggest the existence of a syndrome where the whole is more than its parts None PEW Inflam CVD PEW + Inflam PEW + CVD Inflam + CVD Inflam + CVD + PEW

20 CRP: Is it a risk factor or just a a risk marker? CJASN 2008

21 Lancet 2005 Raised CRP is linked to metabolic syndrome (geometric and mean, 95%CI) cardiovascular CGC risk (0.006) 1.81 ( ) CGT However, associations between CRP and health outcomes 0.26 (0.005) 1.70 ( ) might be affected by reverse causation or confounding. CAC GGT Common haplotypes for the CRP region Estimated frequency (SE) 0.30 (0.006) Up-regulation of cytokines as a result of obesity or kidney disease. Environmental factors, such as smoking and socioeconomic positions (0.003) Plasma CRP (mg/l) 2.03 ( ) 1.39 ( ) To generate unconfounded and unbiased estimates of any causal association between CRP and the metabolic syndrome. CRP haplotypes not associated with potential confounding variables.

22 2008 Conclusion: CRP is a risk marker not a risk factor. Inflammation may rather play a causal role in vascular disease via upstream effectors.

23 CJASN 2008

24 IL-6 Predicts Poor Outcome in ESRD Bologa et al. AJKD 1998 NDT 2002 NDT 2004 AJKD 2005

25 Pro-atherogenic Effects of IL-6 IL-6 exacerbates early atherosclerosis in mice (Huber et al Arterioscler Thromb Vasc Biol 1999) High IL-6 reflects endothelial dysfunction (Nawawi et al. Atherosclerosis 2003) IL-6 decrease adiponectin mrna (Bruun et al Am J Physiol Endocrinol Metab 2003) IL-6 IL-6 expression is involved at the fibrous plaque stage (Elhage et al. Atherosclerosis 2001). Chlamydia pneumoniae IgA and elevated level of IL-6 may synergize to accelerate coronary artery disease.(jha et al. J Cardiol 2008) Polymorphism in the IL-6 promoter region is associated with markers of subclinical atherosclerosis (Hulkonnen et al. Atherosclerosis 2008)

26 Catabolic Effects of IL-6 Stimulates breakdown of muscle protein (Cederholm et al AJCN 1999) Promotes cancer cachexia (Argiles et al. Curr Opin Clin Nutr Metab Care 2003) IL-6 infusion reduces food intake and gastric emptying (McCarthy Res Nurs Health 2000) Activation of IL-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 receptor antibody inhibit muscle atrophy in IL-6 transgenic mice (Tsujinaka T et al. JCI 1996) IL-6 inhibits the secretion of IGF-1 (Barbieri et al. Am J Physiol Endocriln2003)

27 Variants in the IL-6 Gene is Associated with Vascular Disease and Metabolic Syndrome Diabetes 2000 Diabetes 2004 JASN 2006

28 Multiple Inflammatory Pathways Contribute to the Development of CVD Could the development of gene chips help us to identify risk patients? Lymphotoxin-α and IL-6 gene variants independently predicted risk for CVD among dialysis patients.

29 Classical Pro-inflammatory Cytokines are not the Sole Mediators of Muscle Loss TWEAK TWEAK Many studies induces show skeletal that that muscle neutralization atrophy of of through one one or or inhibition more of of the the of of the classical the ubiquitinproteasome cytokines does and and not not NF-κB lead lead systems to to amelioration of of muscle atrophy. Newly described member of of the the TNF TNF superfamily which induce cellular growth and and proliferation angiogenesis osteoclastogenesis stimulation of of apoptosis FASEB 2007

30 Levels of TWEAK Modulate the Effects of Inflammation on Outcome in Prevalent Dialysis Patients IGF-1, ng/ml Patients survival Crude mortality P<0.05 P<0.05 Low P<0.05 IL 6, high stweak Low IL 6, low stweak High IL 6, low stweak High IL 6, high stweak 50 Log rank Low 0[χ2]: 27.2, High p< Low 2 High 3 TWEAK TWEAK TWEAK TWEAK Low IL-6 High IL-6 Months Adjusted Mortality stweak plasma levels may be associated with Low IL 6, low stweak cardiovascular and Low all-cause IL 6, high stweak mortality in HD patients High IL 6, low stweak with Patients survival systemic inflammation High IL 6, high stweak through pathways that may relate to increased muscle Likelihood Ratio [χ2]: 79.13, p< wasting. TWEAK may be a major mediator of skeletal Months muscle loss in inflamed disease states. Carrero et al. CJASN 2008

31 CJASN 2008

32 Pentraxin 3 - a New Kid on the Block Interleukin-6 Toll-like receptor TNF-a IL-1β Mononuclear cells Fibroblasts Endothelial cells Adipocytes (?) Short pentraxins CRP SAP Long pentraxins PTX3 Opsonization Inflammation tuning Complement activation Resistance to pathogens

33 CJASN 2007 Sensitivity Sensitivity Pentraxin-3, ng/ml ,0 50,0 25,0 7,5 5,0 2,5 0,8 0,5 0,3 IL-6 CRP PTX-3 Rho=-0.54, p< ,8 2,5 5, 0 7,5 25,0 50,0 75, GFR, 1- ml/min Specificity

34 Correlations Between PTX3, Urinary Albumin Excretion and Endothelial Function 5000 Type-2 DM with albuminuria but normal renal function U-Albumin, mg/24 hours Suliman et al. Submitted 2007 CKD 5 patients CJASN 2008 Rho=0.22; p= ,8 2,0 4,0 6,0 8,0 20,0 40,0 60,0 PTX3, ng/ml

35 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 mg/day. Open label study The study was registered in clinicaltrials.gov as NCT ,00 delta PTX3 (%) -20,00-40,00-60,00-80,00-100,00 RSqLinear=0,336-20,00 0,00 20,00 40,00 60,00 delta flow-mediated dilatation (%) Yilmaz et al. CJASN 2009

36 Which Way To Go Regarding Treatment? There will never be a silver bullet

37 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

38 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 Silent ischemic heart disease Intercurrent clinical events Short daily HDal Peridontal disease Failed kidney transplant Volume overload Inflammatory diseases Unpure dialysate Infectious complications of haemodialysis access Conventional HDal Thrombosed fistula or graft Panichi, V. et al. Nephrol. Dial. Transplant : Bioincompatible membranes Ayus, J. C. et al. JASN 2005;16: Bioincompatible dialysis fluids Peritonitis Hemodiafiltration Nutritional intervention Physical training Pharmacological intervention

39 Novel Approaches to the Treatment of Inflammation-Related Wasting in Dialysis act via endorphin receptors Cytokine Enhancing inhibiting prostaglandin releasing synthesis cell synthesis inhibiting cytokine production Strasser et al. J Clin Oncol 2006 Blocking synthesis Anticachectic cytokines (IL-10, IL-15) Procachectic cytokines (IL-6, TNF) Favouring action JASN 2007 Blocking action R Target cell R Lancet 2003 Intracellular signaling pathway Protein AA Argilés et al. Drug Discovery Jan 2008

40 A man should never speak longer in public than he can make love in private

41 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.

42 Welcome to the ISBP 2009 Stockholm Date: Sept 2009

43 Art is I - Science is We Claude Bernard