Cardiovascular Biomarkers in CKD and in ESRD. Alberto Ortiz, MD, PhD IIS-Fundacion Jimenez Diaz Madrid, Spain

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1 Cardiovascular Biomarkers in CKD and in ESRD Alberto Ortiz, MD, PhD IIS-Fundacion Jimenez Diaz Madrid, Spain

2 Accelerated aging in ESRD CKD patients: CVD mortality USRDS: Levey et al. Am J Kidney Dis 1998 ERA/EDTA: de Jager DJ et al. JAMA 2009

3 Outline Biomarkers Inflammation CKD-MBD Cardiac injury/stress Other The issue of time course Multimarker approaches Clinical trials

4 Cardiovascular Biomarkers Risk stratification + therapeutic decission making Preclinical CV disease: IMT/endothelial dysfunction Prediction of CV events Prediction of CV mortality Prediction of total mortality

5 What we need What we have Observational associations between biomarkers and outcomes Clinical trials that explore outcomes of biomarker-guided or biomarker-targeted therapy Neutralizing anti-troponin Ab? Anti-IL-6 strategies?

6 The quiz: mark the correct link Biomarker SEXY!!!!! discovery Biomarker validation NOT SEXY!!!!!

7 The quiz: mark the correct link Biomarker SEXY!!!!! discovery Biomarker validation NOT SEXY!!!!!

8 Current and novel prognostic biomarkers of mortality in ESRD Alkaline phosphatase Calcium Fetuin A FGF23 25-hydroxyvitamin D Parathyroid hormone Phosphate Albumin Pentraxin-3 E-selectin Fibrinogen Gelsolin HGF ICAM1/VCAM1 Interleukin 6 Mannose-binding lectin Myeloperoxidase Soluble CD14 Soluble CD154 TNF Soluble Fas TWEAK NT-proBNP and BNP Troponin I Troponin T ADMA AGEs Bicarbonate Glycemia Homoarginine Homocysteine Lipoprotein a Neuropeptide Y Norepinephrine p-cresol Serum lipid levels Triiodothyronine Ortiz, A. et al. Nat. Rev. Nephrol. advance online publication 1 November 2011

9 Current and novel prognostic biomarkers of mortality in ESRD CKD MBD Alkaline phosphatase Calcium Fetuin A FGF23 25-hydroxyvitamin D Parathyroid hormone Phosphate Protein energy wasting and inflammation Albumin Pentraxin-3 E-selectin Fibrinogen Gelsolin HGF ICAM1/VCAM1 Interleukin 6 Mannose-binding lectin Myeloperoxidase Soluble CD14 Soluble CD154 TNF Soluble Fas TWEAK Myocardial injury/dysfunction NT-proBNP and BNP Troponin I Troponin T Metabolic and other ADMA AGEs Bicarbonate Glycemia Homoarginine Homocysteine Lipoprotein a Neuropeptide Y Norepinephrine p-cresol Serum lipid levels Triiodothyronine Ortiz, A. et al. Nat. Rev. Nephrol. advance online publication 1 November 2011

10 Current and novel prognostic biomarkers of mortality in ESRD CKD MBD Alkaline phosphatase Calcium Fetuin A FGF23 25-hydroxyvitamin D Parathyroid hormone Phosphate Protein energy wasting and inflammation Albumin Pentraxin-3 E-selectin Fibrinogen Gelsolin HGF ICAM1/VCAM1 Interleukin 6 Mannose-binding lectin Myeloperoxidase Soluble CD14 Soluble CD154 TNF Soluble Fas TWEAK Myocardial injury/dysfunction NT-proBNP and BNP Troponin I Troponin T Metabolic and other ADMA AGEs Bicarbonate Glycemia Homoarginine Homocysteine Lipoprotein a Neuropeptide Y Norepinephrine p-cresol Serum lipid levels Triiodothyronine Biomarkers beyond current guideline therapy targets Predictive of mortality Confirmed by several groups Ortiz, A. et al. Nat. Rev. Nephrol. advance online publication 1 November 2011

11 Inflammation CKD-MBD Metabolic abnormalities Other Cause of CV injury ctroponin T ctroponin I NT-proBNP BNP Cardio Stress/Injury Vascular Consequence of CV injury

12 Biomarkers Inflammation IL-6 CRP Fetuin A CKD-MBD Cardiac injury/stress Other Outline The issue of time course Multimarker approaches Clinical trials

13 Sources of inflammation IL-6 Acute-phase reactants Göran K. HanssonN Engl J Med 2005;352:

14 Causes of inflammation during dialysis Failed kidney transplant in situ Biofilm (grafts, catheters, hemodialysis machine) Silent (encapsulated) infection of arteriovenous or arterial grafts Chronic obstructive uropathies Calciphylaxis Cholesterol emboli Peripheral arterial disease Silent cardiac ischemia (myocardial ischemia, stroke) Congestive heart failure Ischemic ulcers, neuropathic and venous ulcers Chronic obstructive pulmonary disease Inflammatory bowel disease Periodontal inflammation Arthritis Hepatitis Major surgery Underlying renal diagnosis (infected cysts in autosomal dominant polycystic kidney disease) vasculitis relapse, sinusitis, otitis Discitis, osteomyelitis, endocarditis Urinary tract infection/urosepsis, biliary sepsis Septicemia, any cause (foreign material) Malignancy, de novo and recurrent Wanner, C. et al. Nephrol. Dial. Transplant. 22 (Suppl. 3), iii7 iii12 (2007).

15 Other sources of inflammation IL-6 Acute-phase reactants Positive. e.g. Pentraxins C-reactive protein Serum amyloid A [SAA] Pentraxin 3 (Macrophages) Negative: albumin, fetuin A Göran K. HanssonN Engl J Med 2005;352:

16 Other sources of inflammation IL-6 Acute-phase reactants Positive. e.g. Pentraxins C-reactive protein Serum amyloid A [SAA] Pentraxin 3 (Macrophages) Negative: albumin, fetuin A Göran K. HanssonN Engl J Med 2005;352:

17 90 ambulatory, adult HD, adjusted for age, albumin, BMI Lower IL-6 tertile Higher IL-6 tertile

18 Other sources of inflammation IL-6 Acute-phase reactants Positive. e.g. Pentraxins C-reactive protein Serum amyloid A [SAA] Pentraxin 3 (Macrophages) Negative: albumin, fetuin A Göran K. HanssonN Engl J Med 2005;352:

19 Inflammation Markers, Adhesion Molecules, and All-Cause and Cardiovascular Mortality in Patients with ESRD: Owing to its stronger link to outcomes, IL-6 seems to be the best option for risk stratification in dialysis patients. However, being that the risk estimate bycrp for all-cause and CV death is reasonably close to that of IL-6, CRP may be considered as a cheap alternative to IL-6 in everyday clinical practice Tripepi,J Am Soc Nephrol 16: S83 S88, 2005

20 Other sources of inflammation IL-6 Acute-phase reactants Positive. e.g. Pentraxins C-reactive protein Serum amyloid A [SAA] Pentraxin 3 (Macrophages) Negative: albumin, fetuin A Göran K. HanssonN Engl J Med 2005;352:

21 Low fetuin A s associated with inflammation 312 stable HD patients Lancet 2003; 361:

22 Low fetuin A is associated with mortality

127 ESRD, biomarkers measured at start of dialysis therapy, followed up f 26 months (range, 1 to 66 months) Multivariate analyses show that in patients with ESRD, mortality is

23 127 ESRD, biomarkers measured at start of dialysis therapy, followed up f 26 months (range, 1 to 66 months) Multivariate analyses show that in patients with ESRD, mortality is predicted best by S- Alb, IL-6, and fetuin A levels, but not by hs-crp level. IL-6 level may be the most reliable predictor of mortality in patients with ESRD. Am J Kidney Dis 47:

24 Inflammation biomarkers Inflammatory cytokines and proteins, posiitve acute phase reactants and negative acute phase reactants may provide information on outcomes Il-6 provides the most predictve power and CRP is a cheapaer alternative Area under the ROC curve (discrimination for mortality in HD): 0.59 to 0.74 in different studies assessing IL-6, CRP or fetuin A In general their contribution to risk assessment beyond simple clinical risk scores has not been addressed Formal proof is needed that their systematic use leads to improved outcomes

25 Biomarkers Inflammation CKD-MBD Outline FGF23 Alkaline phosphatase Cardiac injury/stress Other The issue of time course Multimarker approaches Clinical trials

26 Early decrease in Klotho and increase in FGF23 in human CKD Decreased in CKD stage 1 John GB et al. AJKD 2011

27 Inflammatory cytokine reduce Klotho in renal tubular cells NFκB inhibition prevents Klotho dowregulation Moreno et al. JASN 2011

28 FGF23 and Klotho in kidney tubular cells Kuro-o M. Korean Journal of Internal Medicine. 2011

29 Gutierrez et al. N Engl J Med 2008;

30 Elevated circulating FGF23 levels associated with LVH in human CKD Intramyocardial FGF23 induces LVH in mice Faul et al. Clin Invest. 2011;121(11):

31 Akaline phosphatase Persy VP et al. Kidney Int 2011

32 3-yr cohort of 73,960 HD patients Regidor Am Soc Nephrol 19: , 2008

34 Biomarkers Outline Inflammation CKD-MBD Cardiac injury/stress Troponins BNP, NT-proBNP Other The issue of time course Multimarker approaches Clinical trials

35 Cardiac troponins

36 ctnt and ctni following myocardial ischemic injury

37 Prognostic Value of Troponin T and I Among Asymptomatic ESRD Patients. A Meta-Analysis Elevated Troponin T identify a ESRD patients who have poor survival. The prognostic usefulness of troponin I remain unclear, largely because of the lack of standardization of assays. ctnt ctni Khan, Circulation. 2005;112:

38 NT-pro-BNP and mortality in HD 150 Asymptomatic HD patients Satyan, AJKD 2007

39 ctnt and NT-proBNP are associated with mortality in HD 134 HD patients Sommerer Eur J Clin Invest 2007; 37 (5):

40 PalazzuoliVascular Health and Risk Management 2010:

41 Cardiac injury/stress biomarkers Steady state BNP, NT-pro-BNP and ctnt increased in CKD They provide prognostic information which is additive to that of echocardiography ctni assay less standardized Area under the ROC curve (discrimination for mortality in HD): 0.59 to 0.71 Formal proof is needed that their systematic use leads to improved outcomes

42 Biomarkers Inflammation CKD-MBD Cardiac injury/stress Other ADMA T3 Outline The issue of time course Multimarker approaches Clinical trials

43 Fliser NDT 2001

44 ADMA and CV events 225 HD patients Zoccali C, et al. Lancet 2001;358:

45 Low FREE triiodothyronine and survival in ESRD 200 HD patients Zoccali Kidney Int 2006

46 Inflammation and free triiodothyronine in ESRD C Zoccali Kidney International (2006) 70,

47 Outline Biomarkers The issue of time course Multimarker approaches Clinical trials

48 Meuwese, C. L. et al. Nat. Rev. Nephrol. 76 (2011);

49 228 HD patients 3-month observation period Prediction of mortality by single or averaged determinations Snaedal Am J Kidney Dis 53:

50 Trimestral variations of CRP and IL6 are associated with survival in HD 201 prevalent HD patients CRP IL-6

51 Outline Biomarkers The issue of time course Multimarker approaches Same family biomarkers Different family biomarkers Interaction of biomarkers Clinical trials

52 Same family biomarkers Additional inflammatory biomarkers may not lead to a significant gain in predictive power for mortality Zoccali, C., J. Am. Soc. Nephrol. 17, S169 S173 (2006).

53 Different family biomarkers Combined use of inflammation. myocardiopathy and endothelial dysfunction biomarkers for prognostication in HD Combined tertile-based score CRP/BNP Third vs first tertile HR 2-3 CRP/ADMA Mallamaci KI 2005

54 Combined use of inflammation. myocardiopathy and endothelial dysfunction biomarkers for prognostication in HD Mallamaci KI 2005

55 Interaction of biomarkers: TWEAK TNF superfamily cytokines and receptors TNF Cytokines FasL/Apo1L/CD95L Receptors TNFR1 TNFR2 Fas/Apo1/CD95 TRAIL/Apo2L TWEAK/Apo3L (TNFSF12) DR4/TRAILR1 DR5/TRAILR2 Fn14/TWEAKR (TNFRSF12A)

56 TWEAK, its receptor Fn14, and interaction with inflammation Cell death Inflammation Winkles. Nature Rev Drug Disc 2008

57 Inflammed Inflammation increases Fn14 expression Inflammed

58 Single dose administration of BIIB023 (Anti-TWEAK) MCP-1

59 Outline Biomarkers The issue of time course Multimarker approaches Clinical trials

60 Clinical trials The fact that we can identify a high risk does not imply that we can treat that high risk to prevent an event

61 Clinical trials Phosphate binders decrease FGF23 in CKD stage 3 (Gonzalez Parra, Ortiz et al. NDT 2011) FGF23-guided targeting of phosphate overload??

62 Summary Novel biomarkers have the potential to refine risk stratification based on standard risk scores and to guide therapy in HD patients Biomarkers of CKD-MBD, inflammation and myocardial injury/ dysfunction A multimarker approach holds potential for refining prognosis To date, no biomarker has had sufficient full-scale testing, such as in a proper clinical trial, to qualify as a useful addition to standard prognostic factors or to guide therapy in CKD patients Ortiz, A. et al. Nat. Rev. Nephrol. advance online publication 1 November 2011

Cardiovascular Mortality: General Population vs ESRD Dialysis Patients

Cardiovascular Mortality: General Population vs ESRD Dialysis Patients Annual CVD Mortality (%) 100 10 1 0.1 0.01 0.001 25-34 35-44 45-54 55-64 66-74 75-84 >85 Age (years) GP Male GP Female GP Black GP