Cardiac Troponin Assays

Troponin Elevation in Chronic Kidney Disease

Given that the prevalence of chronic kidney disease (CKD) in the United States reached 15 percent in 2008, how to interpret troponin levels in this population is an important issue.^{10, 11} We listed a description of the stages of CKD in Table 1. Of note, even more recently, there are new guidelines for classifying CKD that incorporate albuminuria: http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO_2012_CKD_GL.pdf

Table 1

Stages of chronic kidney disease.

Patients with CKD (particularly those with end-stage renal disease [ESRD]) have a greater prevalence of persistently-elevated cardiac troponin when compared with patients who do not have CKD. Although somewhat controversial, reduced renal clearance most likely is not the primary mechanism for troponin elevation in CKD, but rather it represents a marker of myocardial injury.^{12, 13} The intact troponin molecule is large and it is unlikely that the kidneys are primarily responsible for clearance from serum. However, work by Diris et al. suggests that the troponin molecule is degraded into smaller fragments, which can be detected by the assays and are small enough to be filtered by the kidneys. This mechanism may contribute to the elevation of troponin in severe renal failure.¹⁴ Despite this, Ellis et al.¹⁵ did not observe a statistically significant difference in the half-life and the elimination rate constant of troponin I in patients with myocardial infarction (MI) and ESRD when compared with patients with MI and normal kidney function.

As with non-CKD patients, we must interpret elevated troponin levels in patients with CKD in the context of one's pre-test probability for suspecting an ACS event. Elevated levels may also be due to cardiac injury associated with chronic structural heart disease (e.g., CAD, heart failure, etc.), which is highly prevalent among CKD patients, rather than from acute ischemia, especially when the levels do not change rapidly over time.¹⁶ Among patients without suspected ACS, potential reasons for detectable small increases in troponin include micro-infarctions, microvascular disease, subendocardial ischemia associated with left ventricular hypertrophy and diastolic dysfunction, and nonischemic cardiomyopathic processes, all of which are more common in patients with CKD.

Use of Troponin for the Diagnosis of Acute Coronary Syndrome in Patients With Chronic Kidney Disease (Background for Key Question 1)

In patients with symptoms of ACS, without other causes for increased troponin, clinicians use elevated troponin levels (along with clinical factors) to diagnosis MI as outlined by the Global Task Force's Third Universal Definition of MI (Table 2).¹⁷

Table 2

Definition of myocardial infarction according to 2012 Third Universal Definition.

The diagnosis of ACS among patients with CKD (especially those with ESRD) can be particularly challenging. Electrocardiograms (ECGs) are frequently abnormal in CKD patients (indicating left ventricular hypertrophy, intraventricular conduction delay, wide QRS, etc.), which can reduce the sensitivity/specificity of detecting ischemia.¹⁸ Also, baseline troponin levels are often not known in patients with CKD on initial presentation, making it hard to define elevated troponin levels (increased troponin is considered, along with symptoms and other clinical factors, in diagnosing ACS, as per the global definition of MI). Whether clinicians should use an alternative threshold, other than the 99^th percentile, of elevated cardiac troponin when assessing patients with CKD is unknown. Since not all CKD patients will have elevated levels, high cut-off values will disadvantage those who do not have elevated levels. Therefore, using alternate cutpoints may not be preferable.

On the other hand, the patterns of changes in troponin levels (rise, fall, and magnitude of change) can also be very helpful for clinicians in distinguishing ACS from non-ACS in symptomatic patients. The National Academy of Clinical Biochemistry¹⁹ has recommended that for patients with ESRD and suspected ACS, a diagnosis of acute MI (Type I) should require a dynamic change in troponin levels of greater than 20 percent within 9 hours (with at least one value above the 99^th percentile).¹³ However, clinicians should also consider the timing of presentation from the onset of symptoms. If the patient presents late in the course of ACS, testing could take place during the “plateau phase,” and clinicians may miss the rise/fall pattern. Although widely applied in the guidelines, researchers have not yet studied this 20 percent rule in a vigorous evidence-based fashion and compared it with other degrees of change or the use of a single elevated value in the context of high pre-test probability.

No consensus exists about whether the diagnostic criteria for MI using troponin levels should be different for patients with CKD and those without CKD. It's also unclear whether elevated baseline troponin levels make it more difficult to diagnose ACS in patients with ESRD than in patients with milder forms of CKD.

The following clinical vignette highlights some of the clinical diagnostic dilemmas: The patient is a 68-year-old man with a history of diabetes and CAD who has had remote coronary artery bypass surgery. He has CKD (creatinine 1.8 mg/dL) and previously had a troponin I level of 0.06 mcg/L on his last admission. He is admitted to the hospital with pneumonia but repeated tests of troponin indicate a level of 0.24 mcg/L. He is short of breath but has no chest pain and his ECG shows a left bundle branch block (old). What is the clinical significance of his newly elevated troponin? Should he additionally be managed for ACS?

Use of Troponin Level as a Management Strategy for Patients With Chronic Kidney Disease and Acute Coronary Syndrome (Background for Key Question 2)

Frequently, clinicians use troponin levels, along with clinical factors, to stratify patients according to risk when a diagnosis of non-ST-elevation MI (NSTEMI)/unstable angina is likely. Clinicians usually treat patients at high risk for ACS with an “early invasive” strategy (i.e., diagnostic angiography with the intent of revascularization), while clinicians may treat patients with low-to-intermediate risk of ACS with an “initially conservative” (i.e., selectively invasive) management strategy.²⁰

The “troponin hypothesis” suggests that patients with elevated troponin levels (troponin-positive) are likely to have more thrombus burden, complex lesions, and be at higher risk for worse outcomes than patients with normal troponin levels (troponin-negative). Therefore, it stands to reason that clinicians should treat troponin-positive patients more aggressively. Results from a general population of patients presenting with ACS (not exclusively CKD), found that even minor troponin elevations identify patients who benefit from an early invasive strategy (compared with initially conservative management).²¹ In addition to an early invasive strategy, the use of glycoprotein IIb/IIIa inhibitors and low-molecular-weight heparin also appear more beneficial in troponin-positive versus troponin-negative patients with suspected ACS.¹³ However, in the Clopidogrel in Unstable Angina to prevent Recurrent Events (CURE) clinical trial of ACS patients, clopidogrel use did not confer a preferential benefit in troponin-positive versus troponin-negative patients. Therefore, the troponin hypothesis may not be applicable to all therapeutic management in ACS.

As with the initial diagnosis of ACS, elevated background troponin levels in patients with CKD may limit the applicability of treatment algorithms that are based on troponin levels in non-CKD populations. Whether elevated background troponin levels in patients with CKD and suspected ACS are associated with differences in the comparative effectiveness of interventions or management strategies is unknown.

Use of Troponin Level as a Prognostic Indicator in Patients With Chronic Kidney Disease Following Acute Coronary Syndrome (Background for Key Question 3)

In addition to their use in diagnosing and managing ACS, studies have examined troponin assays as potential independent risk predictors of morbidity and mortality in populations following an acute ischemic event. Previous reviews and meta-analyses have investigated the prognostic performance of troponin testing in patients with kidney failure, but often excluded studies on patients with ACS.^{22, 23} Therefore, the prognostic significance of elevated cardiac troponin levels with regard to short- and long-term major adverse cardiovascular events (MACE) for patients with both CKD and ACS remains uncertain.

Use of Troponins in Adults With Chronic Kidney Disease Who Do Not Have Symptoms of Acute Coronary Syndrome: A Role for Risk Stratification (Background for Key Question 4)

Patients with CKD are known to be at increased risk for cardiovascular morbidity and mortality. Despite established guidelines for primary and secondary cardiovascular disease prevention (i.e., blood pressure, lipid, and glucose targets), cardiovascular disease remains the number one cause of death for CKD patients. Among asymptomatic CKD patients without suspected ACS, prior studies have shown that chronic elevated cardiac troponin is associated with increased risk of cardiovascular morbidity and mortality.^23-26 For this reason, in May 2004 the U.S. Food and Drug Administration approved the measurement of troponin T in dialysis patients for the express purpose of risk stratification (i.e., prediction of mortality). However, it is unknown whether measuring troponins improves risk prediction when compared with (or used in conjunction with) existing models that are based on traditional clinical and laboratory risk factors. Whether troponin testing improves metrics of discrimination and re-classification of patients into higher or lower risk groups is unknown.

It is also unclear whether clinicians should manage asymptomatic patients with CKD and chronically-elevated cardiac troponin levels differently than patients with CKD who have normal troponin levels.

Types of Troponin Assays and Special Subgroups of Patients With Chronic Kidney Disease (Key Questions 1–4)

There are multiple commercially available troponin assays including cardiac troponin T, troponin I, high-sensitivity troponin T, and high-sensitivity troponin I. Whether all of these troponin assays are equal in distinguishing ACS from non-ACS conditions and prognosticating and risk-stratifying CKD patients (with and without ACS) is unclear.

Furthermore, whether troponin testing leads to changes in management and outcomes among certain subgroups of patients with CKD is also unknown (e.g., categories of CKD stages, dialysis status, age, race, gender, and those with prior history of CAD).

Scope and Key Questions

The purpose of this comparative effectiveness review will be to present information for the appropriate use of troponin levels to guide evidence-based management decisions for patients with CKD. These findings should be useful for a diverse set of contingents including cardiologists, nephrologists, emergency room physicians, and laboratory medicine scientists who use and interpret troponin testing in the clinical management of patients. Findings may also be useful for epidemiologists in tackling research gaps for further studies. We addressed the following Key Questions (KQs) in this review (Figures 1 and 2):

Figure 1

Analytic framework for interpreting troponin as a cardiac marker among patients with chronic kidney disease and suspected acute coronary syndrome. Abbreviations: ACS = acute coronary syndrome; CKD = chronic kidney disease; ESRD = end-stage renal disease; (more...)

Figure 2

Analytic framework for interpreting troponin as a cardiac marker during renal function impairment among patients with chronic kidney disease without symptoms of acute coronary syndrome. Abbreviations: ACS = acute coronary syndrome; CKD = chronic kidney (more...)