Markers Cardio-renali

Università degli Studi di Foggia

Facoltà di Medicina e Chirurgia

Corso di Laurea in Medicina e Chirurgia

Argomenti di patologia clinica

Early biomarkers of acute miocardial and kidney injury

G. Stefano Netti, MD

Clinical pathology

Biomarkers: AMI versus AKI

Diagnosis of AMI

Based on 2 out of 3 of WHO criteria (Circulation, 1979):

• Prolonged chest pain
• "Silent infarct”, Painless infarct
• ECG changes

Lacks sensitivity; serum enzyme concentrations such as CKMB lack sensitivity in diagnosis of perioperative MI.

Protein markers, e.g. troponins, myoglobin, and others are emerging in the 21st century.

Limitation of CKMB

• False positive incidents in perioperative patients without cardiac injury
• False elevations in skeletal muscle injury, marathon runners, chronic renal failure, hypothyroidism
• MI detection not timely enough for thrombolytic intervention; MB peaking takes >12h

Need for new cardiac markers

• Timely diagnosis of MI for thrombolytic therapy
• Identify successful reperfusion after thrombolysis in MI
• Diagnosis of perioperative MI
• Early diagnosis of MI in ED
• Expedite triage of patients in ED
• Appropriate use of ICU beds
• Timely management of thrombolytic therapy
• Missed diagnosis of AMI by ED physicians

Cardiac markers of the 21st century

• MB isoenzyme
• Brain natriuretic peptide
• CKMM
• Ischemia modified albumin isoforms
• C-reactive protein
• CKMB isoforms
• Myoglobin
• Troponin I
• Troponin T

Ideal marker to detect AMI

• High concentration in myocardium
• Absence from non-myocardial tissues
• High sensitivity and specificity in circulation
• Rapid release into blood following myocardial injury
• Remains in blood several days to allow detection
• Blood levels correlate with extent of myocardial injury and prognosis
• Rapid, simple, and automated commercial assays available

Role designed for marker in dx & mgt based on clinical studies and peer-reviewed literature.

Troponins

Regulatory proteins in striated muscle responsible for calcium-modulated interaction. Exist in a number of isoforms, cardiac-specific forms immunologically separable:

• Troponin T (TpnT)
• Troponin I (TpnI)

Troponin release kinetics

Pattern of release in MI is biphasic. Detectable in blood 4-12 h, similar to CKMB, peaks 12-38 h, remains elevated for 5-10 days.

Sensibilità e specificità di un test

Sensibilità 100%, Specificità 100%: Tutti i soggetti ammalati sono positivi al test, tutti i soggetti positivi al test sono ammalati.

ROC Curve for Tpn T

Plot of Sensitivity (TP) vs 1-specificity (FP). Used for establishing the best discriminator for cTpnT for predicting AMI. Best discriminator µg/L point is 0.2 at 9h after onset of AMI.

ROC Curve for Tpn I

Temporal pattern of CKMB vs Tpn I. CKMB and Tpn I profiles in AMI.

Algoritmo diagnostico nelle sindromi coronariche acute

Diagnosis of AMI in the Troponin Era, based on ESC/ACC’s redefinition of MI (JACC, 2000): Typical rise and fall of Troponin or CKMB with one of the following:

• Ischemic symptoms
• Development of Q wave on ECG
• ST-segment elevation/depression
• Coronary artery intervention
• Pathologic (morphologic) findings of AMI

Myoglobin

Oxygen binding protein of cardiac and skeletal muscle (MW=17,800 Da). Rapid release from infarcted area over some limited time, rapid transport to serum. May rise significantly within 1-2 h of muscle cell damage and after onset of AMI. Rapid renal clearance, return to normal level within 24 h.

Conditions for acute myocardial infarction

• Open heart surgery
• Skeletal muscle damage, muscular dystrophy, inflammatory myopathies
• Renal failure, severe uremia
• Shock and trauma

Clinical usefulness of myoglobin

• Slow technology (RIA) in the past had limited extensive clinical use as a cardiac marker
• Rapid monitor of success of thrombolytic therapy
• Negative predictor of MI

Due to poor specificity, levels do not always predict myocardial injury.

Marker responses to MI

• A = myoglobin or CKMB isoforms
• B = cardiac troponin
• C = CKMB
• D = cardiac troponin after unstable angina

Brain natriuretic peptide (BNP)

Both BNP and NT-proBNP levels in the blood are used for screening and diagnosis of acute congestive heart failure (CHF) and may be useful to establish prognosis in heart failure, as both markers are typically higher in patients with worse outcomes. The plasma concentrations of both BNP and NT-proBNP are also typically increased in patients with asymptomatic or symptomatic left ventricular dysfunction.

There is no level of BNP that perfectly separates patients with and without heart failure.

BNP: albero decisionale

Paziente con dispnea:

• Esame obiettivo, Rx torace, ECG
• Livelli di BNP
• BNP <100 pg/mL: HF molto improbabile
• BNP 100-500 pg/mL: Sospetto clinico di HF o HF molto probabile (2%) storia pregressa di HF?
• BNP >500 pg/mL: HF probabile (90%)
• Valore soglia di BNP raccomandato 100 pg/mL

Biomarkers: AMI versus AKI

AKI: A common, serious problem

• AKI is present in 5% of all hospitalized patients, and up to 30% of patients in Intensive Care Units (ICUs)
• The incidence is increasing at an alarming rate
• Mortality rate >50% in dialyzed ICU patients
• 25% of ICU dialysis survivors progress to end stage renal disease within 3 years
• % of all "discharged dead" with a diagnosis of ARF: 1979: 1.5%, 2002: 15.7%

Acute Kidney Injury (AKI)

AKI Network

"Achilles Heel": Early diagnosis has been the 'Achilles heel' of acute kidney injury (AKI) that has prevented successful treatment.