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 (NTproBNP) 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 3 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 participate...