Cardiac biomarkers in chronic kidney disease - 2

1. Cardiac biomarkers in chronic kidney disease - 2 Dr.

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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.

10. 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.

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

12. 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

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

14. 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

15. 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

17. 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

18. 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

19. 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.

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

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

30. Thank You!