Cardiac biomarkers for the diagnosis and monitoring of cardiovascular disease in the dialysis population

Abstract

Dialysis patients have a 10-50 fold increased risk of cardiac death compared to the general population. Key factors underpinning this heightened risk are fluid overload-induced cardiomyopathy and ischaemic heart disease. Progress in modifying these outcomes has been hampered by our inability to assess patients’ fluid status and cardiac risk in an accurate and dynamic manner. The overarching aim of this thesis is to advance our understanding of the roles of two cardiac biomarkers, the amino terminal fragment of pro-B-type natriuretic peptide (NT-proBNP) and high sensitivity cardiac troponin-T (hs-cTnT), in diagnosing and monitoring cardiovascular disease in the dialysis population. Two multi-centre, prospective cohort studies were performed. The aim of the first study was to estimate the biological variation of NT-proBNP and plasma hs-cTnT in 55 prevalent haemodialysis and peritoneal-dialysis patients, and to use these estimates to derive the critical difference between serial measurements needed to detect a clinically significant change with 90% confidence. Patients were reviewed weekly for 4 consecutive weeks then monthly for a further 4 months. Assessments were conducted at the same dialysis-cycle time point and entailed clinical review, bioimpedance spectroscopy, electrocardiography, hs-cTnT and NT-proBNP testing. Patients were excluded if they underwent a change in cardiac medication, dialysis prescription, ischaemic symptomatology, extracellular volume >1L, new arrhythmia or hospitalisation between visits. 137 weekly and 114 monthly NT-proBNP and hs-cTnT measurements from 42 stable patients were analysed. Between-person(CVG) and within-person(CVI) coefficients of variation were estimated using nested analysis of variance. For weekly measurements CVG, CVI, and the critical difference were 153%, 27%, and -46% and +84% respectively for NT-proBNP, and 83%, 7.9%, and -25% and +33% respectively for hs-cTnT. For monthly measurements CVG, CVI, and the critical difference were 148%, 35%, and -54% and +119% respectively for NT-proBNP, and 79%, 12.6%, 2.4% and -37% to +58% respectively for hs-cTnT. The CVI:CVG ratios for weekly and monthly measurements were 0.18 and 0.24 respectively for NT-proBNP, and 0.10 and 0.16 respectively for hs-cTnT. CVG was not significantly different by dialysis modality, hydration status, history of ischaemic heart disease, NT-proBNP or hs-cTnT concentration, severity of left ventricular hypertrophy, systolic or diastolic dysfunction. Thus, serial NT-proBNP levels need to double or halve and hs-cTnT levels need to increase by at least 20-34% or fall by 17-25% to confidently exclude change due to analytical & biological variation alone. The low CVI:CVG implies the best strategy for applying these biomarkers in dialysis is relative change monitoring after a baseline estimate rather than comparing results to reference intervals. The second study performed was a longitudinal cohort study of 103 prevalent haemodialysis and peritoneal dialysis patients, of whom 78 patients also participated in an echocardiographic sub-study. The aim of the echocardiographic sub-study was to determine the cross-sectional associations between each of plasma NT-proBNP and hs-cTnT, and measures of hydration status, and functional and structural cardiovascular indices. Patients underwent clinical review, bioimpedance spectroscopy, electro- and echo-cardiography, hs-cTnT and NT-proBNP testing. Multivariable analysis found that plasma NT-proBNP was independently associated with hydration status (standardised β=0.313, P<0.01), left ventricular mass indexed to body surface area (standardised β=0.238, P<0.01), residual renal function (standardised β=-0.086, P=0.05), and left ventricular systolic dysfunction assessed using global longitudinal strain (standardised β=0.233, P<0.01) but not using ejection fraction (standardised β=-0.038, P=0.71). Plasma hs-cTnT was independently associated with hydration status (standardised β=0.379, P<0.01), and with pulse wave velocity (standardised β=0.250, P=0.04) in multivariable analysis. These findings suggest that NT-proBNP testing may have a role in monitoring the risk of adverse cardiac events related to hydration state and cardiomyopathy in the dialysis population, and that hs-cTnT testing may have role either alone or together with plasma NT-proBNP in monitoring hydration status in the dialysis population. The aim of the longitudinal cohort study was to determine the longitudinal correlation of plasma NT-proBNP and hydration status assessed using bioimpedance spectroscopy. Patients were reviewed monthly at the same dialysis-cycle time point and underwent clinical review, bioimpedance spectroscopy, electrocardiography, and NT-proBNP testing. 103 patients were assessed for a median of 14-months (IQR 9-22 months) yielding 1431 paired bioimpedance and plasma NT-proBNP measurements. The correlation coefficient between plasma NT-proBNP and hydration status was estimated for each study participant, followed by meta-analysis of the correlation coefficients across the entire study cohort. Plasma NT-proBNP and hydration status were found to be independently correlated across time (r=0.273 (95% CI 0.200-0.342, I2=48.3%), and meta-regression found that the significant correlation between plasma NT-proBNP and hydration did not differ between subgroups of dialysis modality, left ventricular hypertrophy, systolic or diastolic function. These findings support the use of plasma NT-proBNP testing as a means of monitoring hydration state in the dialysis population. The findings presented in this thesis advance understanding of the pathophysiological factors underpinning plasma NT-proBNP and hs-cTnT in the dialysis population and improve interpretation of serial measurements of these biomarkers in clinical practice.