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Cardiovascular Biomarkers in CKD and in ESRD
Alberto Ortiz, MD, PhD IIS-Fundacion Jimenez Diaz
Madrid, Spain
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
• Biomarkers – Inflammation – CKD-MBD – Cardiac injury/stress – Other
• The issue of time course • Multimarker approaches • Clinical trials
Outline
Risk stratification + therapeutic decission making •Preclinical CV disease: IMT/endothelial dysfunction •Prediction of CV events •Prediction of CV mortality •Prediction of total mortality
Cardiovascular Biomarkers
What we have Observational associations between biomarkers and outcomes
What we need Clinical trials that explore outcomes of biomarker-guided or biomarker-targeted therapy
Neutralizing anti-troponin Ab?
Anti-IL-6 strategies?
Biomarker discovery
Biomarker validation
SEXY!!!!!
NOT SEXY!!!!!
The quiz: mark the correct link
Biomarker discovery
Biomarker validation
SEXY!!!!!
NOT SEXY!!!!!
The quiz: mark the correct link
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
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
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
•Biomarkers beyond current guideline therapy targets •Predictive of mortality •Confirmed by several groups
Cause of CV injury Metabolic abnormalities
CKD-MBD
Inflammation
cTroponin T cTroponin I NT-proBNP BNP
Stress/Injury Cardio Vascular
Consequence of CV injury
Other
Outline
• Biomarkers – Inflammation
• IL-6 • CRP • Fetuin A
– CKD-MBD – Cardiac injury/stress – Other
• The issue of time course • Multimarker approaches • Clinical trials
Göran K. HanssonN Engl J Med 2005;352:1685-95
Sources of inflammation
IL-6
Acute-phase reactants
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).
Göran K. HanssonN Engl J Med 2005;352:1685-95
Positive. e.g. Pentraxins C-reactive protein Serum amyloid A [SAA] Pentraxin 3 (Macrophages) Negative: albumin, fetuin A
Other sources of
inflammation
IL-6
Acute-phase reactants
Göran K. HanssonN Engl J Med 2005;352:1685-95
Positive. e.g. Pentraxins C-reactive protein Serum amyloid A [SAA] Pentraxin 3 (Macrophages) Negative: albumin, fetuin A
Other sources of
inflammation
IL-6
Acute-phase reactants
90 ambulatory, adult HD, adjusted for age, albumin, BMI
Higher IL-6 tertile
Lower IL-6 tertile
Göran K. HanssonN Engl J Med 2005;352:1685-95
Positive. e.g. Pentraxins C-reactive protein Serum amyloid A [SAA] Pentraxin 3 (Macrophages) Negative: albumin, fetuin A
Other sources of
inflammation
IL-6
Acute-phase reactants
Tripepi,J Am Soc Nephrol 16: S83–S88, 2005
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
Göran K. HanssonN Engl J Med 2005;352:1685-95
Positive. e.g. Pentraxins C-reactive protein Serum amyloid A [SAA] Pentraxin 3 (Macrophages) Negative: albumin, fetuin A
Other sources of
inflammation
IL-6
Acute-phase reactants
Lancet 2003; 361: 827–33
312 stable HD patients
Low fetuin A s associated with inflammation
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 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 47:139-148.
• 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
Inflammation biomarkers
Outline
• Biomarkers – Inflammation – CKD-MBD
• FGF23 • Alkaline phosphatase
– Cardiac injury/stress – Other
• The issue of time course • Multimarker approaches • Clinical trials
John GB et al. AJKD 2011
Early decrease in Klotho and increase in FGF23 in human CKD
Decreased in CKD stage 1
Inflammatory cytokine reduce Klotho in renal tubular cells
Moreno et al. JASN 2011
NFκB inhibition prevents Klotho dowregulation
Kuro-o M. Korean Journal of Internal Medicine. 2011
FGF23 and Klotho in kidney tubular cells
Gutierrez et al. N Engl J Med 2008;
Faul et al. Clin Invest. 2011;121(11):4393–4408
Elevated circulating FGF23 levels associated with LVH in human CKD
Intramyocardial FGF23 induces LVH in mice
Persy VP et al. Kidney Int 2011
Akaline phosphatase
3-yr cohort of 73,960 HD patients
Regidor Am Soc Nephrol 19: 2193–2203, 2008
Outline
• Biomarkers – Inflammation – CKD-MBD – Cardiac injury/stress
• Troponins • BNP, NT-proBNP
– Other • The issue of time course • Multimarker approaches • Clinical trials
Cardiac troponins
cTnT and cTnI following myocardial ischemic injury
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.
Khan, Circulation. 2005;112:3088-3096
cTnT cTnI
150 Asymptomatic HD patients Satyan, AJKD 2007
NT-pro-BNP and mortality in HD
134 HD patients
Sommerer Eur J Clin Invest 2007; 37 (5): 350–356
cTNT and NT-proBNP are associated with mortality in HD
PalazzuoliVascular Health and Risk Management 2010:6 411–418
•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
Cardiac injury/stress biomarkers
Outline
• Biomarkers – Inflammation – CKD-MBD – Cardiac injury/stress – Other
• ADMA • T3
• The issue of time course • Multimarker approaches • Clinical trials
Fliser NDT 2001
Zoccali C, et al. Lancet 2001;358:2113–2117.
225 HD patients
ADMA and CV events
Low FREE triiodothyronine and survival in ESRD
200 HD patients
Zoccali Kidney Int 2006
Inflammation and free triiodothyronine in ESRD
C Zoccali Kidney International (2006) 70, 523–528
• Biomarkers • The issue of time course • Multimarker approaches • Clinical trials
Outline
Meuwese, C. L. et al. Nat. Rev. Nephrol. 76 (2011);
Snaedal Am J Kidney Dis 53:1024-1033. © 2009
228 HD patients 3-month observation period Prediction of mortality by single or averaged determinations
Trimestral variations of CRP and IL6 are associated with survival in HD
201 prevalent HD patients
CRP IL-6
• Biomarkers • The issue of time course • Multimarker approaches
– “Same” family biomarkers – “Different” family biomarkers – Interaction of biomarkers
• Clinical trials
Outline
Zoccali, C., J. Am. Soc. Nephrol. 17, S169–S173 (2006).
Additional inflammatory biomarkers may not lead to a significant gain in predictive power for mortality
“Same” family biomarkers
Mallamaci KI 2005
Third vs first tertile HR 2-3
Combined tertile-based score Combined use of inflammation. myocardiopathy and endothelial dysfunction biomarkers for prognostication in HD
“Different” family biomarkers
CRP/BNP
CRP/ADMA
Mallamaci KI 2005
Combined use of inflammation. myocardiopathy and endothelial dysfunction biomarkers for prognostication in HD
Interaction of biomarkers: TWEAK TNF superfamily cytokines and receptors
Cytokines Receptors
TNF FasL/Apo1L/CD95L TRAIL/Apo2L
TWEAK/Apo3L (TNFSF12)
TNFR1 TNFR2 Fas/Apo1/CD95 DR4/TRAILR1 DR5/TRAILR2
Fn14/TWEAKR (TNFRSF12A)
Winkles. Nature Rev Drug Disc 2008
Cell death Inflammation
TWEAK, its receptor Fn14, and interaction with inflammation
Inflammed
Inflammed
Inflammation increases Fn14
expression
MCP-1
Single dose administration of
BIIB023 (Anti-TWEAK)
• Biomarkers • The issue of time course • Multimarker approaches • Clinical trials
Outline
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
Clinical trials
FGF23-guided targeting of phosphate overload??
Phosphate binders decrease FGF23 in CKD stage 3 (Gonzalez Parra, Ortiz et al. NDT 2011)
Ortiz, A. et al. Nat. Rev. Nephrol. advance online publication 1 November 2011
• 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
Summary
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