The impact of chronic kidney disease on stroke risk, mechanisms, and outcomes
Keywords: Chronic kidney disease
Stroke
Hypertension

Chronic kidney disease (CKD) has a rapidly rising global prevalence, affecting as many as one third of the population over the age of 75 years. CKD is a well-known risk factor for cardiovascular disease and in particular, there is a strong association with stroke. Cohort studies and trials indicate that reduced glomerular filtration rate increases the risk of stroke by about 40% and that proteinuria increases the risk by about 70%. In addition, CKD is also strongly associated with subclinical cerebrovascular abnormalities, vascular cognitive impairment, and dementia. There are however a number of outstanding questions regarding the relationship between CKD and stroke.
Firstly, the mechanisms underpinning this relationship are currently unclear. CKD is associated with traditional risk factors such as hypertension, diabetes mellitus, and atrial fibrillation, but non-traditional risk factors such as uraemia, oxidative stress, mineral and bone abnormalities, and dialysis-related factors such as changes in cerebral blood flow or cardiac structure are also purported mechanisms. Hypertension is the leading modifiable risk factor for stroke in the general population and is highly prevalent in CKD, but its role has not been systematically examined. Secondly, it is not known which stroke subtypes are most closely associated with CKD. Thirdly, although CKD is associated with greater short- and long-term mortality post-stroke, its impact on initial stroke severity, recovery, and recurrence risk are less clear. Fourthly, it has been hypothesized that cerebral small vessel disease (SVD) and CKD may be part of a multisystem small-vessel disorder, but their association may simply be confounded as a result of shared risk factors (e.g. hypertension) rather than represent a systemic susceptibility to premature SVD. Finally, CKD has also been associated with cognitive dysfunction but it is not known whether this association is independent of cerebrovascular disease.
The aim of my thesis therefore was to determine the role of hypertension in the relationship between CKD and stroke risk. Using the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification, I also aimed to describe which transient ischaemic attack (TIA) and ischaemic stroke subtypes occur most frequently in patients with CKD. I sought to determine whether CKD is associated with worse initial stroke severity and recovery, and whether CKD is independently predictive of recurrent stroke. I aimed to study the age-specific associations of CKD and the overall burden of SVD (total SVD score), as well as individual SVD markers. Lastly, I investigated the association between CKD and dementia before and after TIA and stroke.
The work of this thesis forms two parts. For the first part, I undertook two large and complex systematic reviews and meta-analyses to better describe what data were already available on the relationship between renal function, proteinuria, and stroke. For these reviews, I developed a search strategy, identified >10,000 studies for title and abstract review, and then >400 studies for full text review. I selected studies and extracted study, patient, stroke characteristics, and outcome data according to a pre-defined protocol. I assessed the quality of included studies, and performed all statistical analysis including meta-analysis, sub-analysis, meta-regression and funnel plots for publication bias. I categorized all studies according to a hierarchy of hypertension adjustment.
For the second part of my thesis, I have collected, collated and analysed data from the Oxford Vascular Study (OXVASC), a population-based prospective cohort study. In particular I worked as one of the Clinical Research Fellows at OXVASC and was involved in regular recruitment, assessment and follow up of study patients. I studied a panel of 16 blood biomarkers related to inflammation, thrombosis, atherogenesis, and cardiac or neuronal cell damage in 1297 patients with TIA or ischaemic stroke. Biomarker levels were log-transformed and correlated with eGFR, adjusted for age. All ischaemic events were classified by TOAST subtypes (cardioembolism, large artery disease, small vessel disease, undetermined, multiple, other aetiology, or incompletely investigated). I used logistic regression analysis to determine the relationship between CKD and TIA/stroke subtypes in 2969 patients who presented between April 1, 2002 to March 31, 2017. I also studied initial stroke severity and early recovery measured using the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin scale (mRS), respectively, in ordinal regression analyses in the same cohort of patients. I used Cox proportional hazard models to determine if CKD was an independent predictor of stroke and other vascular event recurrences.
For the third part of my thesis, I focused on the relationship between CKD, subclinical cerebrovascular disease, and dementia in phenotyped cohorts within OXVASC. I investigated the age-specific associations of CKD and total SVD burden (total SVD score) adjusting for age, sex, and vascular risk factors in 1939 consecutive patients with TIA or ischaemic stroke who underwent cerebral magnetic resonance imaging (MRI) from 2004 to 2018. Finally, I examined associations between pre-event dementia and CKD using logistic regression, and between post-event dementia and CKD using both Cox and competing risk regression models (to account for the competing risk of death), adjusted for age, sex, education, cerebrovascular burden (stroke severity, prior stroke, white matter disease), diabetes mellitus, and dysphasia.
There are several clinically relevant findings in this thesis. Firstly, I have shown that the association between CKD and stroke appears to be highly dependent on the method of adjustment for hypertension. The apparently independent relationship between CKD and stroke may be confounded by their shared association with long-term blood pressure burden. Secondly, I have demonstrated that proteinuria is strongly and independently associated with incident stroke risk even after robust adjustment for hypertension, possibly indicating a shared renal and cerebral susceptibility to vascular injury in this subset of patients of kidney disease that is not fully explained by traditional vascular risk factors. Thirdly, I found that correlations between biomarkers related to inflammation and thrombosis with renal dysfunction in the setting of cerebrovascular events were generally modest after adjustment for age, suggesting that putative risk factors such as chronic inflammation or coagulopathy are unlikely to be important stroke mechanisms in patients with CKD. Fourthly, I have shown that there were no independent positive associations between CKD and specific TOAST subtypes which suggests that renal-specific risk factors are unlikely to play an important role in the aetiology of particular subtypes. Fifthly, I have highlighted that CKD is associated with severity of cerebrovascular events (stroke vs TIA; initial NIHSS; 1-month mRS) and that it is independently predictive of stroke recurrence, particularly early recurrence. Sixthly, I have shown how the association of CKD and cerebral SVD is attenuated with adjustment for shared risk factors at older ages, but remains at younger ages, consistent with a shared susceptibility to premature vascular disease. Finally, in patients with TIA and stroke, CKD was not independently associated with either pre- or post-event dementia, suggesting that age, sex, education, and cerebrovascular burden may play a more important role in the aetiology of dementia in CKD than renal-specific neurodegenerative mechanisms.