The Vascular Endothelium in Chronic Renal Failure

Patients with chronic renal failure (CRF) have a 20-fold increased risk of cardiovascular death compared to the general population, with sudden death, cardiac failure and atherosclerotic vascular disease being the commonest underlying problems. For many years it has been postulated that accelerated atherosclerosis occurs in uraemia and that this may be secondary to a multitude of "traditional" cardiovascular risk factors including dyslipidaemia, hypertension, smoking and diabetes mellitus, all of which are prevalent in this population. Other authors have suggested that "non-traditional" risk factors are more important including accumulation of endogenous inhibitors of nitric oxide synthase and homocysteine, hyperparathyroidism, increased oxidative stress and other, as yet unidentified, uraemic factors. Whatever the mechanism, these risk factors are likely to act by causing endothelial damage and dysfunction. The vascular endothelium lies at the interface between the blood and tissues and has several important roles which together prevent atherosclerosis ; control of vessel tone, inhibition of platelet aggregation, control of the passage of cells and macromolecules, inhibition of vascular smooth muscle cell proliferation and inhibition of monocyte adhesion and migration. The majority of these anti-atherogenic effects are mediated by endothelium-derived nitric oxide. Dysfunction of the vascular endothelium is thought to be a key initial event in the development of atheroslcerosis and has been demonstrated in a number of conditions/risk factors including diabetes, hypertension. smoking, dyslipidaemia and ischaemic heart disease. Few studies have examined endothelial function in chronic renal failure. The work presented in this thesis was performed to examine endothelial function in patients with CRF and in particular to examine endothelium-dependent vasodilatation as this is the easiest aspect of endothelial function to study in humans. Using the in vivo method of forearm venous occlusion plethysmography, endothelium-dependent (EDV) and endothelium-independent (EIDV) vasodilatation was assessed in 16 uraemic patients (pre-dialysis and on CAPD) and 18 controls. The order of infusion of drugs (SNP for EIDV and carbachol for EDV) was randomised. Overall there were no differences between the groups but it was apparent that infusion of SNP as the first agent was having a prolonged effect. Thus when 10 patients and controls were examined, in whom carbachol was infused followed by SNP, EIDV was similar but EDV to carbachol was attenuated in the uraemic patients. This pattern suggested endothelial dysfunction in the uraemic patients, with the most likely defect being impaired endothelial NO production, release or effect. No correlates were found in the background laboratory or blood pressure data to predict the response to these agents. Since many authors have postulated that the most important cause of endothelial dysfunction in uraemia is likely to be the accumulation of circulating factors such as asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor, a second in vitro study was performed to further examine endothelial function in CRF. Utilising wire myography, subcutaneous resistance artery function was assessed in 12 uraemic patients and 8 controls, with vessels removed from the uraemic milieu. This study again revealed a significantly attenuated EDV in the uraemic group with normal EIDV to SNP, and the results therefore suggest that endothelial dysfunction in CRF is not readily reversible and is not entirely secondary to a short-lived circulating factor. The study did not completely rule out an effect of ADMA, however, as this agent may accumulate within cells. Together, both studies confirm the presence of endothelial dysfunction in uraemia with the underlying mechanism being unclear. In this myography study, responses to the vasoconstrictors endothelin-1 and noradrenaline were also assessed. Both agents had a tendency to a greater and more long-lasting effect in the uraemic group compared to controls, perhaps reflecting reduced counterbalancing endothelial NO production or increased vessel wall smooth muscle. As blood pressure in uraemic patients on renal replacement therapy is usually dependent on blood volume a further small study was undertaken to examine the effects of altered fluid balance on endothelial responses in CAPD patients. Recruitment for this study proved difficult and results are presented for just 3 patients. Endothelium-dependent vasodilatation and EIDV were assessed using forearm strain- gauge plethysmography before and after a 2kg weight gain. Results were conflicting and no clear pattern was observed. A larger study is required to assess the hypothesis that increased blood volume is associated with reduced endothelium-dependent vasodilatation and consequent hypertension. Since the increased cardiovascular risk of patients on dialysis persists following renal transplantation, a final study was performed to examine endothelial function in renal transplant recipients. (Abstract shortened by ProQuest.)