INTRODUCTION — Levels of cardiac enzymes are principally utilized to help assess the presence or absence of acute myocardial injury. Abnormal elevations in the serum concentrations of these enzymes may be the key diagnostic element in determining admission to the hospital and/or coronary care units. They are also increasingly being used as predictive markers for short- and long-term adverse outcomes, particularly among those presenting with acute coronary syndromes. The principal cardiac enzymes are cardiac troponin T (cTnT), cardiac troponin I (cTnI), and the MB isoenzyme of creatine kinase (CK-MB). (See "Troponins and creatine kinase as biomarkers of cardiac injury".)

Coronary artery disease is highly prevalent in patients with end-stage renal disease (ESRD). As a result, the accurate interpretation of serum concentrations of these enzymes is extremely important. (See "Clinical manifestations and diagnosis of coronary heart disease in end-stage renal disease (dialysis)".)

Issues relating to the clinical use of cardiac troponins and CK-MB in patients with renal failure are presented in this topic review. Their use in patients with normal renal function and the effect of renal failure on hepatic and pancreatic enzymes are discussed separately. (See "Troponins and creatine kinase as biomarkers of cardiac injury" and "Serum enzymes in patients with renal failure".)

TROPONINS — Cardiac troponins I and T are cardiac regulatory proteins that control the calcium-mediated interaction of actin and myosin. Because of their increased specificity compared with CK-MB and other markers, serum troponins are the preferred marker for the diagnosis of myocardial injury among patients with normal renal function. (See "Troponins and creatine kinase as biomarkers of cardiac injury".)

Elevated values in asymptomatic patients — The appropriate use of these enzymes in patients with renal insufficiency is less clear, since elevations in serum troponins are commonly observed in patients with renal insufficiency who do not have clinical evidence of myocardial damage [1,2]. Although newer assays are somewhat more accurate, these tests also demonstrate increased troponin levels, particularly cTnT, in those without myocardial necrosis.

In the largest study of 733 asymptomatic patients with ESRD, an extremely high percentage had increased troponin levels, despite the use of the latest generation assays [3]; the percentages varied markedly with the utilization of different cutoff criteria:

• The use of cutoff values that were greater than that observed among 99 percent of a general reference population (which were defined as 0.01 and 0.1 µg/L for cTnT and cTnI, respectively) resulted in 82 and 6 percent of dialysis patients with increases in cTnT and cTnI values, respectively.
• The use of the lowest values to give 10 percent imprecision (which were 0.03 and 0.5 µg/L for cTnT and cTnI, respectively) resulted in 53 and 1 percent of patients defined as having increased values, respectively.
• The use of values that had been optimized for detection of myocardial infarction (which were 0.1 and 0.6 µg/L for cTnT and cTnI, respectively) resulted in 20 and 0.4 percent of dialysis patients having increased values, respectively.

The exact mechanisms underlying these increased levels are unclear [1]. Possible reasons include elevations of troponin with left ventricular hypertrophy, endothelial dysfunction, loss of membrane integrity with leakage of the free cytosolic troponin pool, stretch-mediated troponin release, and impaired renal excretion [4]. The finding that cTnT is more frequently elevated than cTnI among asymptomatic patients with renal insufficiency may be due to the relatively higher levels of an unbound cytosolic pool of cTnT and its higher molecular weight [5].

These observations illustrate the difficulty in accurately interpreting elevations in cardiac troponins, particularly cTnT, in patients with renal insufficiency. Despite this, the measurement of specific forms of troponin may provide clinically useful information in this patient population:

• Serial elevations in troponins may be diagnostically accurate in patients with suspected myocardial infarction.
• Elevations in serum troponins may be highly prognostic for both short-term and long-term outcomes in asymptomatic patients as well as those presenting with suspected myocardial ischemia.

Use in prognosis

Asymptomatic patients — There is an increasing evidence that elevations in serum troponin levels in stable asymptomatic patients with ESRD are predictive of worse long-term cardiovascular outcomes and poor survival [6-17]. A 2005 meta-analysis of 28 studies consisting of 3931 asymptomatic dialysis patients noted that elevated cTnT levels were associated with a poor prognosis [13]. At a mean follow-up of 23 months, increased cTnT levels (defined as >0.1 ng/mL) were associated an increased mortality risk (RR of 2.67, 95% CI, 2.17 to 3.20). Conclusions related to increased cTnI levels could not be performed due to the wide variety of assays and different cut points.

The reasons for the association between elevated levels of troponins and a poor prognosis among asymptomatic patients with ESRD are unknown. Some reported associations include the following:

• A correlation between increased troponin levels and diffuse coronary artery disease in this patient population has been reported [8,17,18]. A similar association has been reported in asymptomatic patients with chronic kidney disease who are not dialysis-dependent [19]

• In a study of dialysis patients on the kidney transplant wait list, increased cTnT levels correlated with abnormal echocardiographic findings and decreased survival [16].

Acute coronary syndromes — Elevations in cTnT levels may also be highly prognostic for both short-term and long-term outcomes among patients with renal insufficiency who present with acute coronary syndromes. As an example, serum cTnT and the creatinine clearance were evaluated in patients with acute coronary syndromes enrolled in the GUSTO-IV trial [20]. Elevated cTnT independently predicted short-term prognosis in all patients. Patients with a creatinine clearance ≥58.4 mL/min and an elevated cTnT had a small but significant increased risk of myocardial infarction or death compared to those with a comparable creatinine clearance and no cTnT elevation (7 versus 5 percent). Similarly, patients with a creatinine clearance in the lowest quartile and an elevated cTnT had an increased risk of the same outcomes (20 versus 9 percent).

An important limitation of this study was that most patients had mild to moderate renal dysfunction. Only 25 percent had a creatinine clearance below 58 mL/min and only 2 percent had values below 10 mL/min. Thus, it is uncertain if these results apply to patients with an acute coronary syndrome who have ESRD.

Elevations in cTnI levels among patients presenting with possible acute MI and renal dysfunction also identify a population at increased risk for adverse events [21].

Use for diagnosis of MI — When used as a possible marker for acute myocardial infarction, a number of studies have reported a large percentage of false positive elevations of serum cTnT in patients with ESRD [3,22-25]. In the large study cited above, 82 percent of asymptomatic dialysis patients had elevated cTnT levels when the cutoff value was 0.01 µg/L [3]. The elevations may also be quite marked, with levels being 14 times above normal in one patient [26].

However, the exact percentage of patients with elevated cTnT levels depends to a large degree on the exact population studied, and the specific assay and cutoff value used. As an example, the Enzymum assay for cTnT may be associated with a lower false positive rate for acute myocardial infarction compared with the first generation enzyme-linked immunoassay (ELISA) (17 versus 71 percent) [22].

By comparison, serum cTnI is less likely to be associated with false elevations in patients with end-stage renal disease and suspected myocardial damage [3,22,23,27-31]. As examples:

• The enhanced accuracy of cTnI for the detection of myocardial damage was confirmed in a prospective study of 56 patients with renal failure and suspected recent myocardial infarction [24]. Nonenzymatic determination of the presence or absence of new myocardial damage was assessed via the history, physical examination, electrocardiography, and, if clinically indicated, echocardiography, nuclear imaging, and/or coronary angiography. Positive tests were defined as greater than 0.8 µg/L for cTnI and more than 5 percent for CK-MB when total CK levels were elevated. The sensitivity and specificity for the detection of myocardial injury was 94 and 100 percent for cTnI, respectively, compared to only 44 and 56 percent for CK-MB.
• The diagnostic accuracy of cTnI, CK-MB, and myoglobin was evaluated in a prospective study of 817 consecutive patients with possible acute MI [31]. Patients were not excluded due to renal dysfunction. Stratification of patients into quartiles by creatinine clearance was performed, with the fifth group being 51 dialysis patients. cTnI levels were independent of measures of renal function, while CK-MB and myoglobin levels correlated with creatinine clearance. No trend in false positive elevations of cTnI was observed.

CREATINE KINASE — Plasma concentrations of total CK are elevated in approximately 30 to 70 percent of dialysis patients [32,33]. The underlying reasons for this increase are probably multifactorial; these include a skeletal myopathy, intramuscular injections, deficiencies of vitamin D or carnitine, muscle trauma, and reduced clearance [32-35]. Among patients with ESRD, elevations of total CK are usually less than three times the upper limit of normal.

CK isoenzymes consist of dimers of M and B chains; as a result, three isoenzymes are found: CK-MM, CK-MB, and CK-BB [36]. (See "Troponins and creatine kinase as biomarkers of cardiac injury".)

CK-MB fraction — In the absence of ESRD and acute myocardial damage, less than 5 percent of total CK is present as the MB fraction. With myocardial injury, the fraction of CK-MB among patients without renal failure rises beyond this level in a well-described temporal pattern. (See "Troponins and creatine kinase as biomarkers of cardiac injury".)

However, approximately 30 to 50 percent of dialysis patients without evidence of myocardial injury exhibit an elevation in the MB fraction (defined as greater than 5 percent) [22,27,33,36]. The percentage is even higher among those with elevations of total CK. As an example, one longitudinal study of 18 stable hemodialysis patients found that 72 percent had at least one elevated level of total CK [33]. More than 80 percent of these individuals also had at least one increased fraction of CK-MB.

Although usually elevated, the CK-MB fraction is usually less than 8 percent among dialysis patients without evidence of myocardial injury. Thus, interpretation of an elevation of CK-MB alone in dialysis patients with atypical chest pain is not reliable.

Other CK isoenzymes — Increased serum levels of CK-MM and CK-BB are not used in diagnosing myocardial damage in patients with or without renal failure; however, elevations in these isoenzymes may suggest other conditions, such as a myopathy with increased values for CK-MM:

CK-MM — The levels of CK-MM are increased in a significant percentage of dialysis patients. Possible etiologies include myopathy, hepatitis, and deficiencies of vitamin D and/or carnitine [32-35].

CK-BB — In a review of patients with chronic renal failure, CK-BB was universally present in the serum of 13 of 14 peritoneal dialysis patients, all 60 hemodialysis patients, and nearly all of those with a serum creatinine concentration 4.5 mg/dL (398 µmol/L) [37]. By comparison, serum CK-BB was absent in nine patients with acute renal failure (eight of whom needed dialysis) and in 10 renal transplant patients.

RECOMMENDATIONS

Use in prognosis — Although not currently part of the routine evaluation, consideration may be given to measurement of serum troponin levels, particularly cTnT, among asymptomatic patients with end stage renal disease as it may provide significant prognostic information [1,3,38]. Further study is required to determine whether a more aggressive approach to treatment should be employed among asymptomatic patients with ESRD and elevated cTnT and (possibly) C-reactive protein levels.

Use for diagnosis of MI — Determination of myocardial injury in dialysis patients using CK-MB and cTnT (ELISA method) alone is often associated with false positive results, possibly leading to unnecessary hospitalization of a significant number of patients. The most specific marker for myocardial damage among patients with ESRD appears to be serial measurements of cTnI.

We recommend serial measurements of cTnI or, if not available, cTnT, and CK-MB to help determine the presence or absence of myocardial injury among patients suspected of an acute myocardial infarction. A clinically appropriate sequential rise in these values may be most consistent with acute myocardial necrosis in patients with renal failure [1]. By comparison, the finding of elevated but unchanging values is less consistent with new myocardial damage.