Cardiac biomarkers and health-related quality of life in new hemodialysis patients without symptomatic cardiac disease

Patients with ESRD have diminished scores in the physical domains of health related quality of life. Biomarkers for adequacy of dialysis, mineral metabolism and inflammation correlate poorly with these domains, although nutritional biomarkers do correlate.

In hemodialysis patients without prior symptomatic cardiac disease elevated baseline Troponin T levels, but not B type natriuretic peptide, are associated with deterioration in the physical domains of quality of life.

Health Related Quality of Life (HRQOL) is a consistent predictor of mortality in end stage renal disease (ESRD) ( [1–3]). Patients with ESRD have consistently diminished HRQOL compared with matched controls without ESRD, most pronounced in physical function and vitality ( [4]). Biomarkers are regularly tracked in dialysis units, but biomarkers for adequacy of dialysis (KT/V), mineral metabolism and inflammation correlate poorly with HRQOL, although nutritional biomarkers associate with the physical domains in HRQOL ( [4]). Although HRQOL scores are substantially higher in hemodialysis (HD) patients without prior symptomatic cardiac disease compared to unselected hemodialysis patients ( [5, 6]) the relationship between cardiac biomarkers, such as N terminal pro-B type naturetic peptide (NT-proBNP) and troponin T, and HRQOL is uncertain.

Cardiovascular events, particularly heart failure and atherosclerotic events have a major impact on HRQOL in ESRD ( [7]). Hemodialysis patients who have not experienced these events may have elevated troponin T, a marker of myocardial injury, or elevated NT-proBNP, a marker of left ventricular (LV) wall stress ( [8]). To determine whether these cardiac biomarkers associate with poor HRQOL or predict deterioration in HRQOL we analyzed troponin T and NT-proBNP levels in incident HD patients, without prior cardiac failure or ischemic heart disease events and without overt cardiac dilation (N = 596), followed for 2 years in a multinational, blinded, randomized controlled trial ( [8, 9]), in whom HRQOL was measured at baseline and serially during follow-up using the SF-36 and FACIT fatigue questionnaires ( [5]).

We hypothesized that cardiac biomarkers would predict deterioration in the physical domains of HRQOL, independent of other baseline clinical characteristics. The objectives of this report are to quantify the associations between traditional biomarkers and cardiac biomarkers, measured at baseline in incident HD patients without symptomatic cardiac disease, and baseline measures of physical function, vitality, and fatigue, together with short-term (24 weeks) and long-term (1 and 2 years) changes in these domains.

The cohort studied in this paper was enrolled in a randomized trial of correction of anemia with erythropoietin ( [9]). The design, methods, randomization, and epoetin dosing protocols have been reported previously ( [9]). Patients were randomly assigned to one of the following hemoglobin (Hb) targets: 9.5 to 11.5 (low target) or 13.5 to 14.5 g/dl (high target). Patients were masked to treatment assignment, as were their doctors. Mean Hb levels at the end of the initial 24-week titration phase were 13.3 and 10.9 g/dl, respectively. During the maintenance phase, from weeks 24 through 96, corresponding mean Hb levels were 13.1 and 10.8 g/dl. Cardiac structure constituted the primary study outcome, and no difference was observed between the two groups ( [9]). Consequently, for the purpose of this article, all patients were included as one cohort. The study was centrally coordinated from St. John’s, Canada, for Canadian patients and Manchester, England, For European patients.

Local independent ethics committees or institutional review boards approved the study protocol form before study initiation. The study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. All patients gave informed consent before study enrollment.

The mean score in the general population for SF-36 physical function was 86 and for dialysis patients 41, ( [12, 6]), whereas in our patients without symptomatic cardiac disease the score was 67 ( [5]). For SF-36 vitality the comparable scores were 66, 43 and 58, and for FACIT fatigue the mean score in the general population was 80, in diabetic CKD patients 30 ( [13]) and in our group 70. Clearly the presence of symptomatic cardiac disease is associated with HRQOL in dialysis patients. The current paper demonstrates that in dialysis patients without symptomatic cardiac disease at baseline few biomarkers were consistently associated with the deterioration in quality of life scores, but cardiac damage revealed by high Troponin T levels was associated with deterioration. It is important to note that the associations between change in HRQOL scores and high troponin T levels were not confounded by the prior occurrence of symptomatic heart failure or ischemic heart disease, or by the presence of LV dysfunction defined by a high LV volume. The fact that this group was relatively healthy is confirmed by the observation of an annual mortality of 5%, substantially lower than that in unselected hemodialysis patients ( [9]).

In the study by Apple et al. ( [14]) using the 99th percentile of a healthy reference population to define an elevated troponin T level, 82% of unselected asymptomatic hemodialysis patients had a level above this value ( > 0.01 ng/ml). In our study the interquartile range was 0.01 to 0.05 ng/ml. It is likely that elevated troponin T levels in dialysis patients reflects not only myocardial injury and ischemia but also myocardial fibrosis ( [15]). A meta-analysis suggested that an elevated troponin T > 0.1 ng/ml can identify a subgroup of dialysis patients with poor survival and higher risk of death ( [16]). In a previous paper we reported that higher troponin T levels were predictive of subsequent cardiovascular events or death in our selected cohort, but that this association was not independent of age, diabetes, systolic blood pressure or NT-proBNP levels ( [8]). The current paper lends support to the belief that high troponin levels are not innocuous, and that they are associated with deterioration in the physical domains of HRQOL. Whether this effect is mediated via the development of subsequent cardiac events which cause a decrease in HRQOL or by the degree of myocardial injury present at baseline is difficult to determine. The fact that high Troponin T levels were associated with lower HRQOL scores at baseline and after short-term follow-up suggests that the latter hypothesis is tenable, particularly as only 4% of cases developed a cardiovascular/death event by six months (myocardial infarction, myocardial ischemia, angina pectoris, cardiac failure, pulmonary edema, cerebellar infarction, cerebral hemorrhage, cerebral vascular disorder, or death) ( [8]). Whether this interpretation is correct requires further investigation.

BNP or NT-proBNP is a cardiac biomarker reflecting LV wall stress that may occur secondary to volume expansion, pressure overload and increased wall tension ( [15]). In our previous paper NT-proBNP in this selected group was an independent predictor of baseline LVMI, of increase in LVMI over time, and of the subsequent occurrence of cardiovascular events or death ( [8]). Although higher BNP levels may be associated with left ventricular hypertrophy and with systolic dysfunction, in stable hemodialysis patients with normal LV function on echocardiography high BNP levels are likely the result of blood volume expansion and decrease with reduction in post dialysis “dry” weight ( [17]). In the current paper, high BNP levels were not associated with a decrease HRQOL in the short-term or the long-term.

Limitations of the study include: 1. the study from which the data originated was not designed to evaluate the impact of cardiac biomarkers on HRQOL. 2. It was not possible to confirm that baseline Troponin T levels were predictive of HRQOL independent of subsequent cardiac events. However the group studied limited confounding induced by the presence of symptomatic cardiac disease and of echocardiographic systolic dysfunction. 3. It is possible that patients who did not have repeat measurements of HRQOL may be systematically different but this would likely lead to underestimate of the true association between the biomarkers and HRQOL.

We conclude that in a group of patients without prior symptomatic cardiac disease at baseline or without a dilated LV, elevated troponin T levels, but not elevated BNP levels, on starting hemodialysis are associated with deterioration in the physical domains of HRQOL.