Aldosterone and the cardiovascular complications of chronic kidney disease

Cardiac mortality and morbidity is a significant problem in the renal failure population. For some, their renal dysfunction is a consequence of their cardiac failure or general vascular disease; for others it develops and progresses over the course of their renal disease. Uraemic Cardiomyopathy is a group of particular cardiac abnormalities that are found in renal failure; left ventricular hypertrophy, ventricular dilatation and left ventricular systolic dysfunction. Left ventricular hypertrophy is the commonest of these and occurs in 75% of those starting dialysis. Pathological examination of these hearts reveals prominent cardiac fibrosis and expansion of the ventricular muscular wall. Uraemic cardiomyopathy is more common as renal function deteriorates but doesn’t occur in all patients requiring renal replacement therapy. Therefore it has been proposed that factors other than uraemia and uraemic toxins probably contribute to this pathological process. The renin-angiotensin-aldosterone system is one of the possible contributing factors. Animal studies and more recently clinical studies have added weight to this theory. Brilla and Weber published a set of landmark papers in 1992, demonstrating an increase in cardiac fibrosis in rats treated with an aldosterone infusion. However, these finding were only present in rats fed a high sodium diet. They also appear to be independent of hypertension; another known cause of left ventricular hypertrophy. Evidence in humans is more difficult to prove and remains varied in outcome. A recent study in a hypertensive population found a positive correlation between aldosterone serum levels and left ventricular mass. Evidence in renal failure is even more limited and it is this situation that we have focused on in our study. Transforming growth factor beta is a proposed down-stream signalling molecule of the renin-angiotensin-aldosterone system in cardiac fibrosis/left ventricular hypertrophy. However this is not the only signalling pathway that is under investigation and at present the evidence is equivocal. This Thesis incorporates three separate but related studies. The West of Scotland Kidney Disease Study was a 10 year follow-up analysis of patients initially enrolled in 2005, with a range of renal failure from mild to end-stage, those on dialysis and transplanted patients. As expected survival decreased as renal function declined and survival rates were better in the transplanted group than those on dialysis. However, survival rates in this group of patients were not determined by aldosterone, total renin, aldosterone:renin ratio, left ventricular mass or ejection fraction. Our study did confirm previous evidence that urinary protein excretion greater than 1 g/day was associated with a significant increase in mortality over the 10 year follow-up. The Aldosterone Study, aimed to identify factors affecting left ventricular mass and aldosterone levels in a renal failure population. Unfortunately no link was identified between aldosterone and left ventricular mass, or surrogate markers of cardiac disease. Also no significant factors affecting the aldosterone levels of these patients were identified. The Rat Slice Study was an experimental model developed in an attempt to replicate ventricular cell interactions and structure that occurs within the body. Rat ventricle tissue slices were used and incubated in media for 48hours. The media was supplemented with different concentrations of aldosterone, water or both to determine the effects of aldosterone and sodium concentration on TGF-β1 production and cardiac fibrosis. Viability of the slices was evident at 48hours although at a much lower level than at the start of the experiment. No increase in cardiac fibrosis or TGF-β1 production was found in any of the groups of tissue slices. In Conclusion, the three studies undertaken found no definitive evidence for the role of aldosterone or TGF-β1 in cardiac fibrosis/left ventricular hypertrophy. This was true of both the uraemic and non-uraemic states