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Disentangling the Multiple Links Between Renal Dysfunction and Cerebrovascular Disease Dearbhla Kelly,‍ ‍Peter Malcolm Rothwell

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Disentangling the Multiple Links Between Renal Dysfunction and Cerebrovascular Disease Dearbhla Kelly,‍ ‍Peter Malcolm Rothwell Cerebrovascular disease J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2019-320526 on 11 September 2019. Downloaded from REVIEW Disentangling the multiple links between renal dysfunction and cerebrovascular disease Dearbhla Kelly, Peter Malcolm Rothwell ► Additional material is ABSTRact consequences of renal dysfunction,and diseases that published online only. To view, Chronic kidney disease (CKD) has a rapidly rising can cause both CKD and stroke. please visit the journal online (http:// dx. doi. org/ 10. 1136/ global prevalence, affecting as many as one-third jnnp- 2019- 320526). of the population over the age of 75 years. CKD is ASSOciatiONS BETWEEN CKD AND a well-known risk factor for cardiovascular disease CEREBROVASCULAR DISEASE Centre for the Prevention and, in particular, there is a strong association with Stroke risk of Stroke and Dementia, stroke. Cohort studies and trials indicate that reduced Nuffield Department of Clinical There is conflicting evidence about whether CKD, Neurosciences, University of glomerular filtration rate increases the risk of stroke by specifically low estimated glomerular filtration Oxford, Oxford, UK about 40% and that proteinuria increases the risk by rate (eGFR), is a risk factor for stroke indepen- about 70%. In addition, CKD is also strongly associated dent of traditional cardiovascular risk factors. In Correspondence to with subclinical cerebrovascular abnormalities, vascular a meta-analysis of 22 634 people from four popu- Dr Dearbhla Kelly, Centre for cognitive impairment and dementia. The mechanisms lation-based longitudinal studies, individuals with the Prevention of Stroke and responsible for these associations are currently unclear. 2 Dementia, Nuffield Department an eGFR of <60 mL/min/1.73 m had an incidence of Clinical Neurosciences, John CKD is associated with traditional risk factors such as rate of 10.3 stroke events per 1000 person-years Radcliffe Hospital, Oxford OX3 hypertension, diabetes mellitus and atrial fibrillation, but compared with 3.4 events per 1000 person-years in 9DU, UK; Dearbhla. Kelly@ ndcn. non-traditional risk factors such as uraemia, oxidative those without; however, this apparent excess risk ox. ac. uk stress, mineral and bone abnormalities, and dialysis- of stroke was no longer statistically significant after Received 24 March 2019 related factors, such as changes in cerebral blood adjusting for conventional vascular risk factors (HR Revised 29 July 2019 flow or cardiac structure, are also postulated to play 1.17, 95% CI 0.95–1.44; p=0.13).5 Accepted 7 August 2019 a role. Kidney disease can also impact and complicate However, this attenuation of risk association may copyright. the treatments used in acute stroke and in secondary simply have been the result of inadequate statistical prevention. In this review, we will outline our current power, as a larger meta-analysis of 33 prospective understanding of the epidemiology and pathophysiology studies with 284 672 participants experiencing of cerebrovascular disease in CKD. 7863 stroke events reported that patients with an eGFR of <60 mL/min/1.73 m2 had a 43% increased risk of stroke in a pooled multivariate-adjusted analysis that adjusted for conventional vascular risk INTRODUCTION factors,6 with an increase in both ischaemic and Chronic Kidney Disease (CKD) affects as many haemorrhagic strokes. as 8-16% of the population worldwide.1 It is Similarly, in the most recent meta-analysis of 83 an increasingly important global health burden, studies (over two million participants), there was an mainly because it is an established risk factor for inverse linear relationship between eGFR and the cardiovascular disease. Compared with the general risk of stroke, with risk of stroke increasing 7% for http://jnnp.bmj.com/ population, cardiovascular diseases such as stroke every 10 mL/min/1.73 m2 decrease in glomerular are more frequent and severe, and are often under- filtration rate (GFR).7 A 25 mg/mmol increase in treated in people with CKD. Even in less advanced the albumin to creatinine ratio (ACR) was associ- stages of CKD, cardiovascular mortality is still ated with a 10% increased risk of stroke. As in the much higher than the incidence of kidney failure.2 previous meta-analysis, the results were consistent Despite improvements in cardiovascular disease across stroke subtypes, by sex or in subgroup strata survival in the general population, the rate of with varying prevalence of vascular risk factors on October 2, 2021 by guest. Protected progress in patients with CKD, especially in those (hypertension, diabetes and smoking), suggesting an who are dialysis dependent, has lagged behind.3 In independent relationship between CKD and stroke particular, CKD contributes to the risk and severity risk. Stroke risk increased linearly and additively of stroke, subclinical cerebrovascular abnormalities with declining GFR and increasing albuminuria. and vascular dementia.4 There is a particularly strong and independent © Author(s) (or their In this review, we will explore the risk, severity association between proteinuria and stroke. In a employer(s)) 2019. Re-use permitted under CC BY. and mechanisms for stroke in CKD. Firstly, we meta-analysis of 10 cohort studies (140 231 partic- Published by BMJ. will discuss the clinical associations between renal ipants, 3266 strokes), participants with proteinuria and cerebrovascular diseases, including isch- had a 71% greater risk of stroke compared with To cite: Kelly D, Rothwell aemic stroke, small-vessel disease (SVD), haem- those without (95% CI 1.39% to 2.10%).8 The PM. J Neurol Neurosurg Psychiatry Epub ahead of orrhagic stroke, vascular cognitive impairment risk of stroke remained high after adjustment for print: [please include Day and dementia. Secondly, we will highlight the other cardiovascular risk factors, but there may Month Year]. doi:10.1136/ mechanisms of susceptibility and injury, including be residual confounders. There is a dose–response jnnp-2019-320526 shared pathophysiology and risk factors, secondary relationship with higher levels of albuminuria Kelly D, Rothwell PM. J Neurol Neurosurg Psychiatry 2019;0:1–10. doi:10.1136/jnnp-2019-320526 1 Cerebrovascular disease J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2019-320526 on 11 September 2019. Downloaded from conferring greater stroke risk. In another meta-analysis, patients pathological mechanisms underlying white matter changes in with macroalbuminuria had a higher risk of incident stroke (rela- CKD. tive risk (RR) 2.65, 95% CI 2.25 to 3.14) compared to that of The Oxford Vascular Study highlighted an age-specific asso- those with microalbuminuria (RR 1.58, 95% CI 1.39 to 1.80).9 ciation between SVD and CKD in 1080 patients with transient ischaemic attack (TIA) and ischaemic stroke.16 CKD was asso- ciated with total SVD score but only in a younger population Stroke outcomes (<60 years) (OR 3.97, 95% CI 1.69 to 9.32; p=0.002). This Patients with CKD tend to suffer more severe strokes with association was diminished but remained after adjustment for worse functional outcomes, morbidity and mortality. This was age, sex, history of hypertension or diabetes, and premorbid demonstrated by the Fukuoka Stroke Registry multicentre study average systolic BP (OR 3.11, 95% CI 1.21 to 7.98; p=0.018). of 3778 patients with first-ever ischaemic stroke.10 On admis- The strong association between CKD and SVD at younger sion, the National Institutes of Health Stroke Scale (NIHSS) ages could indicate a shared genetic vulnerability to premature scores of patients with CKD were significantly higher than cardiovascular disease, accentuated by acquired risk factors such those without CKD. After adjustment for possible confounding as hypertension. factors, including age, baseline NIHSS score, cardioembolic aeti- Subclinical SVD has also been proposed to underlie the asso- ology, blood pressure (BP) on admission, history of hypertension ciation between CKD and cognitive impairment, as patients with or diabetes, thrombolytic therapy and infectious complications, CKD have a tendency to develop a pattern of cognitive dysfunc- patients with CKD had a 49% (95% CI 17% to 89%) greater tion with prominent deficits in executive function, attention, risk of neurological deterioration during their hospitalisation planning and information processing speed, which is typical for (defined as a ≥2-point increase in the NIHSS score), a 138% a vascular cognitive impairment profile.17 18 (95% CI 61% to 257%) greater risk of in-hospital mortality and While intensive glycaemic control is known to reduce the inci- a 25% (95% CI 5% to 48%) greater risk of a Modified Rankin dence and progression of nephropathy in diabetic patients,19 it Scale score of ≥2 at discharge. does not appear to have any impact on cerebral SVD.20 Functional outcomes and stroke mortality are worse in advanced CKD. In a cohort study of 232 236 patients, patients with an eGFR of <15 mL/min/1.73 m2 (not on dialysis) had a 2.5 Intracerebral haemorrhage (ICH) in CKD times greater risk of in-hospital mortality after acute ischaemic CKD is prevalent in nearly one-third of patients presenting with stroke compared with those with normal renal function, even ICH, and it is associated with much worse mortality compared after adjusting for comorbidities and initial NIHSS score.11 This with those with normal renal function.21 The high CKD prev- subgroup of patients also had much lower rates of functional alence rates in those with ICH may be attributable
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