Cardiovascular Biomarkers in CKD and in ESRD Alberto Ortiz ...

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


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

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


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).


Positive. e.g. Pentraxins C-reactive protein Serum amyloid A [SAA] Pentraxin 3 (Macrophages) Negative: albumin, fetuin A

Other sources of

inflammation

IL-6




Other sources of

inflammation

IL-6


90 ambulatory, adult HD, adjusted for age, albumin, BMI

Higher IL-6 tertile

Lower IL-6 tertile



Other sources of

inflammation

IL-6


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



Other sources of

inflammation

IL-6


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


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


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)


• 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

Cardiovascular Biomarkers in CKD and in ESRD Alberto Ortiz ...

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