Cardiac biomarkers in chronic kidney disease - 2

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					  Cardiac biomarkers in
chronic kidney disease - 2
            Dr.
                 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
                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
            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
               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
   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
   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
    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
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.
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.
 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 <3 times ULN)
         • Occasionally 5-10 times ULN



ULN – Upper limit of normal   Daugirdas JT, Handbook of dialysis (2007) 4th ed.
 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

ULN – Upper limit of normal     Daugirdas JT, Handbook of dialysis (2007) 4th ed.
 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 <8% of the total CK value

ULN – Upper limit of normal         Daugirdas JT, Handbook of dialysis (2007) 4th ed.
 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

ULN – Upper limit of normal         Daugirdas JT, Handbook of dialysis (2007) 4th ed.
 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

ULN – Upper limit of normal     Daugirdas JT, Handbook of dialysis (2007) 4th ed.
 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

ULN – Upper limit of normal     Daugirdas JT, Handbook of dialysis (2007) 4th ed.
 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
ULN – Upper limit of normal   Daugirdas JT, Handbook of dialysis (2007) 4th ed.
   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
    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.
   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
    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 2003;59:35-39,
                                    **Nephrol Dial Transplant 1998;13:1709-1712
   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
    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
     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
      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
       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
       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 2011:23, 3–11
         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 2011:23, 3–11
                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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