From The Archives: How to interpret troponins in renal disease?
Please enjoy this post from the archives first posted on October 21, 2009.
By Ivan Saraiva MD
Case: A 68-year-old man, with a history of stable angina and end-stage renal disease treated by hemodialysis for the past three years, presents to the hospital with leg swelling and shortness of breath. He also complains of intermittent chest pain unrelated to exertion. Physical exam reveals bilateral pitting lower extremity edema, pulmonary crackles, and an elevated jugular venous pressure. Initial electrocardiogram is notable for some nonspecific repolarization abnormalities. Troponin I levels drawn at 0, 6, and 12 hours after initial presentation are 0.03-ng/mL, 0.12-ng/mL, and 0.09-ng/mL, respectively. How should this patient be further evaluated and treated?
Many clinicians debate the usefulness of troponin and other biomarkers in patients with impaired renal function for several reasons. Often, patients admitted for non-cardiac problems will have incidentally elevated troponins. On the other hand, patients in heart failure may have positive troponins for any number of reasons, whether due to an acute ischemic myocardial insult or as a consequence of a chronic fluid-overloaded state. Some clinicians even question whether or not elevated troponins represent myocardial injury at all. In each of these cases, concomitant renal disease only further complicates the clinical picture.
Troponin (Tn) subtypes T, I, and C exist together as a protein complex bound to actin thin filaments in both skeletal and cardiac muscle. This complex regulates muscle contraction and relaxation via its interaction with actin and calcium ions released from the sarcoplasmic reticulum of the muscle cells. TnT and TnI have different isoforms in cardiac and striated muscle, which allows laboratory assays that can identify troponins specifically released from injured myocytes in the heart.
Several studies have explored the significance of elevated troponins in patients with concomitant renal disease [1-10]. Up to 80% of patients with low glomerular filtration rates (GFR), and in the absence of acute coronary syndromes or congestive heart failure, have positive values for TnT, regardless of whether or not they receive dialysis treatment. On the other hand, one large study that included more than 700 patients found the prevalence of TnI to be only 0.4-6% depending on the cut-off value chosen . These results suggest that a positive TnT may represent a common and benign incidental finding in patients with impaired renal function, whereas a positive TnI occurs only in the setting of an acute coronary event. However, other studies have demonstrated consistent associations between elevated TnT and hard endpoints such as death and myocardial infarction [2,3,5,6]. Therefore, although chronic kidney disease appears to be nonspecifically associated with positive TnT values, the absolute TnT level may serve as a useful prognostic marker.
The etiology of the increased TnT in renal disease remains unclear. Recently, a few small, but well-designed, studies have attempted to clarify the association. Askoy et al. studied TnT levels in 62 patients with non-ischemic congestive heart failure. Elevated TnT values were associated with a low ejection fraction, severity of heart failure (NYHA class), and low GFR in the initial univariate analysis. However, after adjustment by regression analysis, only a low GFR remained significantly associated with a positive TnT . Going in the same line of thought, Tsutamoto et al. performed a very elegant study measuring the transcardiac TnT gradient by measuring levels in both the aortic root and coronary sinus . They classified 258 patients with congestive heart failure as having either normal or low GFR. Despite the finding of markedly elevated levels of TnT in the patients with low GFR compared to the patients with normal renal function, the transcardiac gradient appeared similar between the two groups. They concluded that the elevated TnT observed in patients with a low GFR occurs as a result of accumulation rather than increased myocardial injury.
In conclusion, evidence suggests that the kidneys clear TnT and thus baseline levels may indeed rise in the setting of a low GFR. Conversely, it appears that elevated TnI values represent myocardial injury in both patients with low GFR and other populations. Keep in mind however that several mechanisms of non-ischemic myocardial injury occur in the setting of renal disease, including fibrotic and infiltrative processes. These may independently result in an elevated TnI even in the absence of an acute ischemic myocardial insult . Despite these conclusions, elevated TnT and TnI remain specific for heart disease and should never be treated as meaningless.
Based on the above discussion, the management of our case patient should proceed as follows. The differential diagnosis for his presentation must account for a fluid-overloaded state, chest discomfort, and positive TnI values. The patient may have suffered an acute coronary event, exacerbation of a chronic heart failure state, or worsening of his renal function leading to fluid-overload. All of these etiologies may account for his elevated troponin. Notably, this case used the values of TnI, the biomarker assumed to be less commonly accumulated in the setting of chronically impaired renal function. Thus, his positive TnI can be more confidently interpreted as specific for an acute myocardial injury. Furthermore, the patient’s TnI displays a peak followed by a downward trend, which increases the likelihood of an acute event and less likely represents a chronically elevated troponin due to renal disease alone.
Dr. Saraiva is a 2nd year internal medicine resident at NYU Medical Center.
Faculty peer reviewed by Robert Roswell MD, NYU Division of Cardiology
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