Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular disease to which conventional cardiovascular risk factors and co-morbidity contribute. Increased arterial stiffness and impaired endothelial function are common features of CKD and recognised markers of cardiovascular risk. In recent years, emerging cardiovascular risk factors - including inflammation, oxidative stress, and a shift in the balance of the vasodilator nitric oxide and vasoconstrictor endothelin systems - have become increasingly important as major contributors to increased cardiovascular complications and may also contribute to arterial stiffness and endothelial dysfunction in CKD. The overall aims of the work presented within this thesis were, therefore, to characterise the contribution of uraemia itself, and conventional and emerging cardiovascular risk factors, to arterial stiffness and endothelial dysfunction, as surrogates for cardiovascular risk, in a group of CKD patients, across a wide range of glomerular filtration rate (GFR) from normal to pre-dialysis, with relatively low comorbidity. Arterial stiffness and endothelial dysfunction were measured by carotidfemoral pulse wave velocity (CF-PWV) and flow-mediated dilatation (FMD), respectively. The first study aimed to assess the reproducibility for one observer with repeated measurements (intra-observer) and for two separate observers (inter-observer) of CFPWV and FMD. I have shown that both inter-observer and intra-observer measurements of CF-PWV and FMD are highly reproducible. Hence, these techniques are therefore suitable to be incorporated into clinical studies. The characteristics of the relationship of plasma and urinary endothelin-1 (ET-1) concentrations to renal function were studied. In this group of CKD patients, plasma ET-1 increased in a linear fashion, whereas fractional excretion of ET-1 increased exponentially as renal function declined. These findings support the role of renally derived ET-1 in renal pathophysiology. In the next study, I showed that arterial stiffness increases incrementally as GFR declines whereas endothelial dysfunction is a feature only of late stage CKD (GFR ≤ 20 ml/min/1.73m²). Age and blood pressure (BP) were the major determinants of both. However, GFR was not an independent predictor of either CF-PWV or FMD in this group of patients, suggesting that uraemia, on its own, is not the main driving force in the development of vascular complications in CKD. Therefore, I further explored the role of emerging cardiovascular risk factors to arterial stiffness and endothelial dysfunction. Whilst, BP remains the strongest determinant of arterial stiffness and endothelial dysfunction, inflammation and asymmetrical dimethylarginine, an endogenous nitric oxide synthase inhibitor, are independent predictors of CF-PWV, and oxidative stress and plasma ET-1 independently predict FMD. Thus, the cardiovascular complications that occur in CKD may be substantially driven by these emerging risk factors. Then, I examined the contribution of the metabolic syndrome to arterial stiffness and endothelial dysfunction in the same group of CKD patients. Irrespective of renal function, CKD patients with the metabolic syndrome have increased arterial stiffness and a trend to impaired endothelial function. Either the presence of the metabolic syndrome or the number of risk factors for it independently predicts CF-PWV and FMD. When risk factors for the metabolic syndrome are considered individually, BP remains an independent determinant of both CF-PWV and FMD. Additionally, waist circumference is also an independent predictor of CF-PWV. These findings suggest that the metabolic syndrome or its individual risk factors maybe targets for intervention to improve cardiovascular outcomes in all stages of CKD. The contributions of arterial calcification to arterial stiffness and endothelial dysfunction were also assessed. I showed that, irrespective of renal function, CKD patients with arterial calcification have increased arterial stiffness and a trend to impaired endothelial function. The findings from the observational studies presented in this thesis support the role of emerging cardiovascular risk factors on arterial stiffness and endothelial dysfunction in CKD. An interventional study using a peptide selective endothelin-A (ETa) receptor antagonist has confirmed this hypothesis. In a group of CKD patients, irrespective of renal function, selective ETA receptor antagonism lowered BP, reduced proteinuria, improved arterial stiffness on top of a standard BP lowering treatment with renin-angiotensin system blockade, and appeared to reduced arterial stiffness independent of its effect on BP. In summary, these studies show that in the absence of diabetes or established cardiovascular disease, CKD patients have increased arterial stiffness and endothelial dysfunction. Elowever, arterial stiffness and endothelial dysfunction are not predicted by renal function. Although the conventional risk factor, BP, is the strongest determinant of CF-PWV and FMD in CKD, the contribution of several emerging cardiovascular risk factors on arterial stiffness and endothelial dysfunction is observed. On the basis of these findings, chronic interventional studies, for instance with endothelin receptor antagonists are now needed.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:726439 |
| Date | January 2010 |
| Creators | Lilitkarntakul, Pajaree |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/24838 |
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