The cerebrovascular effects of end-stage renal disease: from the patient to the population

The incidence of cerebrovascular disease and glomerular filtration rate are inversely related such that by the development of end-stage renal disease the stroke incidence rate is up to 10 times higher than that expected in the general population. End-stage renal disease - the end result of progressive chronic kidney disease - is strongly associated with an increase in ‘conventional’ cerebrovascular risk factors such as hypertension, atrial fibrillation, diabetes and concurrent cardiovascular disease and is further complicated by a burden of renal specific risk factors such as renal replacement therapy (RRT) itself. While the influence of modifiable risk factors such as hypertension and atrial fibrillation are firmly established in the general population, their influence is less clear in those with ESRD. This lack of clarity leads to discrepancies in management, which may affect even acute stroke care. Mortality following stroke in ESRD is high, and the more subtle consequences of cerebrovascular disease are underappreciated. For example, mild to moderate cognitive impairment is present in up to 80% of dialysis patients and the pattern of cognitive loss, its association with cardiovascular risk factors and lack of improvement from greater solute clearance has led most to believe a cerebrovascular mechanism is culprit. Haemodialysis is capable of reducing cerebral blood flow during the dialysis session, but a correlation between intradialytic changes in cerebral blood flow and cognitive function has never been assessed. The studies within this thesis are designed to assess stroke within Scotland’s population focussing on incidence, associations and outcomes in those with ESRD, with particular interest in the association of atrial fibrillation and RRT modality with stroke and determination of equality of care. In the first of the epidemiological studies, utilising in excess of 1000 patients, I demonstrate the high incidence of stroke, and perform survival analyses, demonstrating that age, prior stroke, and diabetes are significantly associated with stroke, whereas hypertension and atrial fibrillation are not. Further, in those with atrial fibrillation there is no demonstrable association with stroke. Atrial fibrillation was, however, found to be significantly associated with death at follow-up. To progress this further, I use national data to perform a competing risk analysis encompassing 5,502 haemodialysis patients: regression analyses provide an insight into the association of atrial fibrillation on pre-stroke death and stroke as outcomes. In this study, atrial fibrillation is found to be a predictor of mortality, but not stroke. Existing data describing the benefit from anticoagulation on stroke risk are varied. Taking the competing risk of death into account provides one explanation for this variation in outcome. In a further study, I examine the association of a ‘non-conventional’ risk factor for stroke: RRT modality. In this study, 4,957 patients newly commencing RRT for ESRD are examined. Performing survival analyses to determine the influence of their selected RRT modality on stroke at follow-up, I employed a technique to adjust RRT modality exposure as a time-dependent co-variable, allowing, on a month-by-month basis, dialysis modality exposure to be accounted for. On multivariable regression, haemodialysis was associated with an increased stroke risk whereas PD was not. In the last of the epidemiological studies, I use propensity score matching to compare 8,757 ESRD patients to a cohort of 61,367 people without ESRD to assess for discrepancies in their acute stroke care pathway. In doing so, I demonstrate that those undergoing dialysis for ESRD are less likely to be undergo thrombolysis, receive antiplatelet, undergo a prompt swallow test or be managed on an acute stroke unit than their matched non-ESRD cohort. Further, death is more common during the index admission in those with ESRD than in those without - whether on dialysis or with a renal transplant. Acknowledging that stroke is more common in those on haemodialysis, and that haemodialysis as a RRT modality appears to increase stroke risk, my final study concentrates on the effect of a single, and ongoing haemodialysis treatment on an individual patient’s cerebral blood flow, cognitive function and cerebral structure in a recruited cohort of 97 participants. Using real-time measures of cerebral arterial flow, I describe intradialytic alterations in cerebral blood flow and correlate this to intra-dialytic variations in cognitive function, demonstrating evidence to support a cerebrovascular mechanism for cognitive dysfunction. Over follow-up, there remained a correlation between change in cerebral arterial flow and cognitive dysfunction, with progression in white matter hyperintensities in those on continued haemodialysis, whereas in those who are transplanted at follow-up there is demonstrable improvement in cognitive function and MRI-based markers of diffusion. In summary, these studies highlight the high incidence of stroke, that haemodialysis as chosen RRT modality increases stroke risk and that the lack of association from warfarin may relate to a lack of association from atrial fibrillation. They have characterised for the first time the discrepancies in stroke care between those on dialysis and the non-ESRD population and one mechanism by which haemodialysis may be responsible for inducing cognitive dysfunction and increasing overall stroke risk