Cardiac biomarkers in chronic kidney disease - 2

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Cardiac biomarkers in chronic kidney disease - 2

• Dr.

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Introduction

• End-stage renal disease (ESRD) patients receiving
  renal replacement therapy have an excess of
  cardiovascular mortality
• Therefore, accurate diagnosis of acute cardiac
  syndromes in these patients is important

Clinical Medicine Research 2006 4 79-84
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Introduction

• Available biochemical markers, especially those
  other than troponins, used to detect myocardial
  injury have been found to be falsely elevated in
  patients receiving maintenance dialysis

Clinical Medicine Research 2006 4 79-84
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Cardiac Enzymes

• Troponins
• The structural proteins of both cardiac and
  skeletal muscles and are responsible for
  regulation of actin-myosin binding
• Cardiac troponins are specifically determined by
  monoclonal antibody assays since they are encoded
  by genes that are different from their skeletal
  counterparts

Clinical Medicine Research 2006 4 79-84
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Cardiac Enzymes

• Troponin T, I, and C are three types of cardiac
  troponins that form the troponin complex
• Both cardiac troponin I (cTnI) and cardiac
  troponin T (cTnT) are very sensitive and specific
  markers of myocardial damage and are used widely
  for this aim
• However, in the absence of a major, clinically
  evident cardiac injury, troponins are found to be
  elevated in several clinical conditions like
  ESRD, sepsis, pulmonary embolism and acute stroke
• Creatine kinase myocardial isoform (CK-MB) is
  another marker commonly used for diagnosis of
  myocardial infarction

Clinical Medicine Research 2006 4 79-84
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ESRD and Cardiac Enzymes

• Renal failure is one of the conditions in which
  serum markers of myocardial damage are falsely
  elevated
• It is well known that levels of
• Creatine kinase,
• CK-MB and
• Myoglobin are altered in patients with uremia

Clinical Medicine Research 2006 4 79-84
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ESRD and Cardiac Enzymes

• In some studies it is demonstrated that elevated
  cardiac troponins are a sign of coronary artery
  disease when these patients were investigated
  invasively by angiography or non-invasively using
  stress cardiac isotopic imaging
• However, there are reports showing that cardiac
  troponins, especially cTnT, might be elevated in
  patients with uremia without a clinically evident
  coronary ischemic event

Clinical Medicine Research 2006 4 79-84
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ESRD and Cardiac Enzymes

• Angina
• May be atypical or not observed due to silent
  ischemia and can be caused by factors other than
  coronary artery disease
• In addition,
• Nonspecific electrocardiogram findings are very
  common in these patients due to electrolyte
  imbalance, left ventricular hypertrophy and drug
  effects
• Therefore,
• The value of specific biochemical markers of
  myocardial injury is crucial to this patient
  population

Clinical Medicine Research 2006 4 79-84
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Acute myocardial infarction (MI)

• In dialysis patients undergoing acute MI,
• the time course of elevations in serum levels of
• creatine kinase (CK),
• aspartate aminotransferase (AST), and
• lactate dehydrogenase (LDH) is presumably similar
  to that in nonuremic patients,
• although no data to this effect have been
  published

Daugirdas JT, Handbook of dialysis (2007) 4th ed.
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Acute myocardial infarction (MI)

• It is of note that measurements of total CK and
  LDH are no longer recommended for the diagnosis
  of MI

Daugirdas JT, Handbook of dialysis (2007) 4th ed.
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Acute myocardial infarction (MI)

• A. Creatine kinase
• Elevated baseline serum total CK level
• Baseline s. total CK values are elevated
  persistently in 10-50 of dialysis patients
• Elevation is usually mild (e.g lt3 times ULN)
• Occasionally 5-10 times ULN

Daugirdas JT, Handbook of dialysis (2007) 4th ed.
ULN Upper limit of normal
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Acute myocardial infarction (MI)

• A. Creatine kinase
• Elevated baseline serum total CK level
• Postulated causes of high levels
• Intramuscular injection of androgens or other
  drugs
• Subclinical myopathies, vitamin D deficiency
• Carnitine deficiency, reduced degradation of
  enzyme

Daugirdas JT, Handbook of dialysis (2007) 4th ed.
ULN Upper limit of normal
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Acute myocardial infarction (MI)

• A. Creatine kinase
• Elevated percentage of CK-MB
• nonuremic patients upto 5 of total serum CK
• 3 30 of dialysis patients without evidence of
  myocardial ischemia have been reported to have an
  elevated of CK-MB
• Recent studies report increase in 5 dialysis
  patients
• When CK-MB is increase in dialysis patients
  without MI, the elevation is slight
• e.g. usually to lt8 of the total CK value

Daugirdas JT, Handbook of dialysis (2007) 4th ed.
ULN Upper limit of normal
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Acute myocardial infarction (MI)

• A. Creatine kinase
• Elevated percentage of CK-BB and CK MM in acute
  renal failure
• Serum levels of these isoenzymes are reportedly
  increased in patients with acute renal failure,
• possibly due to their release from damaged renal
  tubular tissue
• Stable hemodialysis patients, serum CK-BB
  concentration is usually in the normal range

Daugirdas JT, Handbook of dialysis (2007) 4th ed.
ULN Upper limit of normal
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Acute myocardial infarction (MI)

• B. Lactic dehydrogenase
• Increase baseline serum LDH level
• Serum levels of LDH may be elevated (to 3 times
  ULN) in as many as 35 of patients with renal
  insufficiency
• Either due to reduced elimination rate or to
  increased release from damaged renal tissue in
  patients with acute renal failure

Daugirdas JT, Handbook of dialysis (2007) 4th ed.
ULN Upper limit of normal
16
Acute myocardial infarction (MI)

• B. Lactic dehydrogenase
• Human cardiac myosin light chain 1
• Enzyme immunoassay of cardiac myosin light chains
  has been proposed as a sensitive test for MI
• Unfortunately in dialysis patients, serum levels
  of this compound are elevated 40-fold over
  control values
• Accordingly, this test is not useful in the ESRD

Daugirdas JT, Handbook of dialysis (2007) 4th ed.
ULN Upper limit of normal
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Acute myocardial infarction (MI)

• C. Cardiac troponisns
• Cardiac troponin T
• Regulatory contractile protein normally absent
  in blood, and its detection serves as a specific
  and sensitive indicator of myocardial damage
• However, blood toponin T is elevated in over 80
  of dialysis patients with no clinical evidence of
  acute myocardial injury

Daugirdas JT, Handbook of dialysis (2007) 4th ed.
ULN Upper limit of normal
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ESRD and Cardiac Enzymes

• Elevations in cardiac troponins in patients with
  ESRD result from a number of potential sources

Clinical Medicine Research 2006 4 79-84
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ESRD and Cardiac Enzymes

• Cardiac toponin I
• Another cardiac specific regulatory contractile
  protein, elevated blood levels of which are a
  specific indicator of cardiac injury
• However, elevated troponin I levels occur in upto
  8-9 of patients with advanced renal failure in
  the absence of clinical evidence of myocardial
  injury
• Nonetheless, troponin I has been shown to be a
• Reasonably accurate predictor of myocardial
  injury in renal failure patients and
• More specific marker of acute MI than troponin T
  and CK-MB in this population
• Hemodialysis does not significantly change the
  serum levels of troponin I

Daugirdas JT, Handbook of dialysis (2007) 4th ed.
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ESRD and Cardiac Enzymes

• As can be seen, there are many hypotheses, but
  the actual source of elevated cardiac troponins
  in the absence of a demonstrable myocardial
  injury in these patients is not clearly known
• Myopathic skeletal muscle in patients with uremia
  seems to be one of the sources of falsely
  elevated levels of CK-MB
• However, there is no clear reason for elevation
  of cTnI and cTnT without myocardial insult

Clinical Medicine Research 2006 4 79-84
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ESRD and Cardiac Enzymes

• Data derived from the trials evaluating the
  diagnostic power of troponins in patients with
  ESRD for the diagnosis of myocardial damage vary
  widely
• sensitivity for cTnT was reported to be as high
  as 100 and in other studies,
• specificity for cTnI was demonstrated to be as
  high as 100, while other trials showed
• very low percentages of sensitivity and
  specificity for cardiac troponins
• Available data, although not conclusive, suggest
  that
• cTnI has higher specificity for cardiac injury in
  patients with ESRD

Clin Nephrol 20035935-39, Nephrol Dial
Transplant 1998131709-1712
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ESRD and Cardiac Enzymes

• It has been suggested that chronically elevated
  troponin levels represent chronic structural
  cardiovascular disease such as
• prior myocardial infarction, chronic CHF, or
  hypertension in the setting of chronic renal
  failure
• These patients are at higher cardiac risk than
  the normal healthy patient population
• Troponin is still a useful diagnostic marker in
  the setting of chronic renal failure

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ESRD and Cardiac Enzymes

• Dialysis does not affect TnT or TnI levels
• Predialysis and postdialysis levels are
  essentially unchanged
• CK-MB, however, is dialyzable,
• levels are decreased postdialysis
• Therefore,
• A single elevated TnT level in patients with
  chronic renal failure (CRF) and possible acute
  coronary syndrome (ACS) is nondiagnostic for AMI
  in the absence of other findings
• The specificity of TnI is higher than TnT in this
  setting but not conclusive for AMI
• Serial determinations are usually required,
  looking for a rise in the troponin level

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ESRD and Cardiac Enzymes

• Therefore, ascertaining whether or not an
  elevated troponin in patients with chronic renal
  failure represents
• true acute myocardial necrosis/infarction or a
  false-positive result can be difficult
• In those patients with cardiac risk factors who
  are deemed clinically to be at moderate-high risk
  for ACS, the prudent approach would be
• to observe and perform serial cardiac markers
  over 6-9 hours
• In low-risk asymptomatic patients,
• the clinician may decide that the elevated
  troponin result is false positive for AMI in the
  absence of any other findings indicative of ACS

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Cardiac enzymes Prognostic significance

• Elevated cardiac troponins in ESRD, the data are
  conflicting
• In some studies, positive results of cTnT were
  found to have more prognostic importance,
• In others cTnI were found to be more powerful for
  the prediction of future events
• In some studies, combinations of them were shown
  to be good predictors of cardiovascular events,
  while some trials showed no prognostic value of
  positive troponin findings in the follow-up of
  these patients
• But, when looking at the results of all these
  studies,
• The prevalence of elevated levels of cTnT was
  more frequent and seems to have more prognostic
  value than cTnI

Clinical Medicine Research 2006 4 79-84
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Cardiac enzymes Prognostic significance

• The clinical significance of an elevated TnT
  level has been debated
• The largest prospective studies have confirmed
  the association between TnT elevation and cardiac
  mortality
• The GUSTO IV ACS trial revealed that patients
  with renal insufficiency and an elevated TnT had
  the highest overall risk of the composite
  endpoint of death or AMI
• Two other prospective studies have reported that
  an elevated TnT but not TnI portended an
  increased long-term mortality risk
• Whether the increased cardiac risk is in the
  short term (ie, 30 d) or only the long term is
  unclear
• Patients without short-term risk may not require
  hospitalization and potentially could have workup
  completed on an outpatient basis

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Cardiac enzymes Prognostic significance

• An elevated cardiac troponin T more than 0.l mg/l
  is strongly associated with all cause mortality
  in haemodialyzed patients as shown in many trials
• (McLaurin et al., 1997 Dierkes et al., 2000
  Gabr et al., 2004)

Journal of the Saudi Heart Association 201123,
311
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Cardiac enzymes Prognostic significance

• In renal failure elevated cardiac troponin is
  associated with a two- to five-fold increase in
  mortality but
• reduced its sensitivity and specificity in
  suspected CAD
• (Apple et al., 2002 Goldmann et al., 2001 Van
  Lente et al., 1999).

Journal of the Saudi Heart Association 201123,
311
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Conclusions

• In light of the available data, we can conclude
  that
• cTnI is more useful than cTnT and CK-MB for
  diagnosing myocardial injury

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Thank You!