Cardiac troponins in patients with renal failure: what are we measuring and when should we measure it?

Patients with kidney disease have a reduced life span compared with those without renal failure. Cardiovascular mortality accounts for the majority of renal deaths. ¹ Cardiovascular morbidity is also increased: 55% of patients receiving haemodialysis have concomitant congestive heart failure. ²

The elevation of blood cardiac troponin (cTn) concentrations in patients with kidney disease has variously been described as being an analytical false-positive: an example as to why cardiac troponin I (cTnI) was a superior test and to be due to re-expression of cardiac troponin T (cTnT) within the skeletal muscle. ³ Early work showed that both cTnT and cTnI concentrations are elevated in patients with renal failure, even using the relatively insensitive assays available at the time. ⁴ Subsequently, the studies on re-expression were shown to have methodological problems. ⁵ Studies using Western blotting and polymerase chain reaction showed that neither adult cTnT protein nor messenger RNA could be detected in skeletal muscle in renal failure. ^6,7 Finally, it was demonstrated that elevated cTnT and cTnI concentrations were a common finding in patients with end-stage renal disease (ESRD) and were prognostic, although cTnT appeared to be a better marker of a poor prognosis than cTnI. ⁸ The advent of more sensitive cTnI assays has increased the number of patients who have ESRD and a detectable cTnI. ⁹ Meta-analysis has demonstrated that both cTnT and cTnI are prognostic markers in patients with renal failure. ¹⁰

Two papers published in this issue of the Annals confirm that elevated blood cTn concentration is common in patients with renal disease and, more importantly, show that persistent cTn elevation is an adverse prognostic marker: a finding that, with the benefit of hindsight, should not be surprising. ^11,12 Like many obvious things in life, it takes careful and insightful studies to demonstrate what everyone else has overlooked and is apparent with the retrospectoscope. Where do we go now and what remains unanswered?

cTn measurement has proved to be an APT test, analytical factors are well defined, it is plausible and treatment strategies are established, certainly in the patients presenting with chest pain. How do the latter two categories translate in the renal failure population? What about biological plausibility? The mechanism of cTn positivity in patients with ESRD remains poorly understood.

Imaging by dobutamine stress echocardiography demonstrated that an increased cTnT concentration was associated with evidence of global ventricular dysfunction. ¹³ Cardiac magnetic resonance imaging showed a diffuse pattern of damage different from that seen with acute myocardial infarction (AMI). ¹⁴ It is likely that cTn elevation in ESRD is due to diffuse myocardial injury possibly combined with reduced renal clearance.

Exactly what forms of cTn occur in the circulation remains the subject of debate and it is unknown exactly how cTn is cleared from the circulation. Is the presence of circulating cTn in renal failure due to a lack of clearance? Are we measuring fragments of cTn or the intact molecule?

Simple accumulation due to increased renal impairment is questionable as cTn concentration does not correlate with glomerular filtration rate. An increased half life (t _1/2) has been demonstrated in patients undergoing coronary artery bypass grafting (CABG) who also had impaired renal function (38.4 versus 25.1 h). ¹⁵ In the study of Ellis et al. and colleagues, however, using the Dimension RxL cTnI assay, the difference between the observed t _1/2 in AMI patients with ESRD (35.5 h) compared with that among AMI patients with normal renal function (25.9 h) did not achieve significance. ¹⁶

Both cTnT and cTnI are undetectable in urine from AMI/cardiac surgery patients with normal renal function, even in the presence of very high serum concentrations. Conversely, elevated urine cTnT and cTnI were demonstrated in AMI/cardiac surgery patients with impaired renal clearance. Although serum cTnT and cTnI concentrations were increased in patients undergoing haemodialysis, only cTnT was detectable in the urine. ¹⁷ This could reflect the relatively high cTnI cut-off used in this study.

Western blotting studies suggest that fragmentation of both cTnT and cTnI occurs in patients following AMI, CABG and in renal failure. ¹⁸ This suggests that cTn fragments are cleared by the kidney and accumulate in the presence of renal impairment. However, the use of monoclonal antibodies other than those of the Roche assay renders this data questionable. Furthermore, using gel chromatography of serum from AMI and renal patients only intact cTnT has been detected when analysed using the Roche cTnT assay. ¹⁹

In terms of treatment, the recent two papers are thought-provoking. It has been shown that renal transplantation is associated with the disappearance of circulating cTnT in those patients who have a favourable outcome, while those who remain cTnT positive post-transplantation have detectable cardiovascular pathologies. ²⁰ Bozbas et al. ²¹ demonstrated a heterogeneous response with increased cTnI post-transplantation in 47%, a decrease in 18% and no change in 35%. This should be interpreted with some degree of caution due to the use of the high, World Health Organization-derived AMI cut-off for cTn in use at that time. Perhaps the real challenge now offered to renal physicians is to generate treatment strategies that will minimize or abolish cTn elevations in patients with ESRD. Especially when they are followed up.

DECLARATIONS

Competing interests: None.

Funding: No funding was received for this editorial.

Ethical Approval: Not applicable.

Guarantor: POC.

Contributorship: Both authors contributed equally to the editorial.