Mafham, Marion

2018-03-29T12:18:30Z

2018-03-29T12:18:30Z

2009

End stage renal failure is associated with a massively increased risk of cardiovascular disease, and evidence suggests that this increase in risk begins early in the development of chronic kidney disease. This thesis considers the hypothesis that small reductions in glomerular filtration rate (GFR), across the population range, are associated with a clustering of cardiovascular risk factors and increased risk of cardiovascular disease and death. Existing methods to accurately measure GFR are difficult to perform and unsuitable for large studies, while GFR estimated from blood creatinine or cystatin c concentration is inaccurate.

The performance of a new method of assessing GFR, in which total plasma iohexol clearance is measured using dried capillary blood spots, was examined in a crosssectional study of 81 consecutive individuals undergoing routine measurement of GFR. The new blood spot iohexol clearance (BSIC) method (using 3 blood spot samples) assessed GFR accurately compared to traditional iohexol clearance using 3 timed plasma samples (mean±standard deviation [BSIC - reference method]: 1.1±7.7 ml/min/1.73m"); prediction equations to estimate GFR from blood creatinine and cystatin c concentration performed poorly. The results were similar when 2 blood spots (2 and 4 hours) were used, but using only a single 4 hour blood spot resulted in some loss of accuracy.

The feasibility of using the BSIC method when the blood spot sampling is completed by participants at home was assessed in a cross-sectional study of 111 individuals. Following a short training, 100% of participants completed satisfactory baseline samples, 97% returned 2 timed samples through the post and 90% found the procedure acceptable. However, 21% returned small or poor quality blood spots and there was statistical evidence ofrounding-up of the recorded sampling time. Among 106 participants with measurements of BSIC-GFR, GFR estimated from blood creatinine, and cystatin c concentration, one or more measures of GFR were positively correlated with blood high density lipoprotein cholesterol concentration, and were inversely correlated with blood concentrations of triglyceride, C-reactive protein, fibrinogen, and homocysteine. BSICGFR was not more strongly related to cardiovascular risk factors than GFR estimated from blood creatinine concentration (eGFR). GFR estimated from plasma cystatin c concentration was strongly related to measures of body fat, but no relationship was seen with the other GFR measures.

In a meta-analysis of cohort studies assessing the relationship between eGFR and risk of death and cardiovascular events, which included 4 061 003 and 1 372 820 individuals for each outcome respectively, a 30% lower eGFR was associated with a 20-30% increase in risk of each outcome, depending on the type of study examined. However, there was significant heterogeneity between the studies. These overall results may underestimate the impact of lower eGFR among those with chronic kidney disease since, in two large studies together contributing 85% of the deaths, lower eGFR was not associated with increased risk of death until eGFR was below 60 ml/min/1.73m2. In one large study contributing 218 000 deaths, the relative risk of death associated with lower eGFR was larger at younger ages, but eGFR had greater absolute impact at older ages and among those with prior vascular disease. Because eGFR is only weakly related to measured GFR among healthy individuals, these results may underestimate the relationship between 'true' GFR and risk of death and vascular disease.

This work demonstrates an association between measures of GFR and cardiovascular risk factors, and increased risk of vascular disease, although the methods used to assess GFR may have introduced bias. Large scale studies in which GFR is accurately measured are needed. Using the new BSIC method for this purpose is potentially feasible, but further work is required to ensure accuracy when the blood sampling is completed by participants themselves.

http://hdl.handle.net/1842/29245

The University of Edinburgh

Annexe Thesis Digitisation Project 2018 Block 17

Already catalogued

Assessing associations between measures of reduced glomerular filtration rate, abnormal cardiovascular risk factors, and risk of cardiovascular morbidity and mortality

Thesis or Dissertation

Doctoral

MD Doctor of Medicine