| Summary: | Cardiovascular disease in particular heart failure is the leading cause of mortality in the growing epidemic of chronic kidney disease (CKD). In addition to a myriad of risk factors or co-morbidities associated with CKD, there are adverse cardiovascular morphological and functional alterations that complicate these CKD patients who most often have poor exercise tolerance and compromised quality of life. Emphasis on addressing the traditional Framingham risk factors has failed to fully explain the increased risk of premature death in these patients complicated by the fact that some of these risk factors are inversely associated with poor outcome, a phenomena known as ‘reverse epidemiology’. Risk stratifying CKD patients using single surrogate markers such as dyslipidemia and left ventricular hypertrophy undermines the underlying complex processes that are involved in the pathophysiology of cardiovascular disease in CKD. Some of these mechanisms involved accelerated arterial stiffness, excess pressure overload with hypertension, volume overload, endothelial dysfunction, reduced myocardial capillary density, cardiac fibrosis, ventricular stiffness and unspecified uraemic-related factors. Kidney transplantation currently confers a survival advantage over dialysis or any existing drug therapy, most likely due to reduction in cardiovascular death and this could serve as a model by which we could derive insights to the complex cardiac and renal interactions. Although improvement in the resting left ventricular echocardiographic measures following transplantation has been documented, the effect of these alterations on functional cardiovascular reserve and thereby survival have not be demonstrated. Reduced cardiovascular reserve measurable by maximal cardiopulmonary exercise testing (CPET) has been shown to be powerful prognostic indicator in patients with various cardiac diseases but particularly in chronic heart failure patients who have reduced cardiovascular reserve. The primary aim of this thesis is to describe the evaluation of functional cardiovascular reserve by CPET in patients with advanced CKD who are initially waitlisted for kidney transplantation in comparison to subjects with treated essential hypertension who are otherwise healthy. This novel assessment is complemented by the use of vascular applanation tonometry and transthoracic echocardiography. The capability of CPET derived measures obtained prior to kidney transplantation in predicting peri- and post-operative morbidity and identifying those at risk of premature all-cause mortality pre- and post-kidney transplantation are demonstrated for the first time through prospective observational studies described in this thesis. Additional analyses have shown that impaired LV compliance and arterial stiffness in CKD adversely influenced functional cardiovascular reserve. Furthermore, the loss of adaptive LV functional properties in CKD subjects that was uniquely apparent compared to the hypertensive but otherwise healthy cohort has provided a pathophysiological background for understanding the association between kidney failure and reduced cardiovascular reserve. Future work originating from this research endeavour will be to describe prospective time-course correlation between cardiovascular morphology and functional cardiovascular reserve following kidney transplantation. This will allow us to carefully define the degree of changes in these variables and identify factors that hinder cardiovascular recovery. This will generate important insights for new effective cardiovascular strategies and interventions for the CKD population. One of the proposed aims is to produce an integrated measure of important prognostic variables that will be used in future intervention trials. With these insights, cardiovascular risk stratification of patients being worked up for kidney transplantation can potentially be improved.
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