Impact of prior stroke on major clinical outcome in chronic kidney disease: the Salford kidney cohort study

Stroke and chronic kidney disease (CKD) are major world health concerns but their interaction is rarely considered. Cerebrovascular disease is the third leading cause of death in the UK [1]. Due to ageing populations and improved survival after stroke [2], more patients are living with these two comorbidities. Patients with CKD are more likely to suffer severe and recurrent strokes [3, 4]. For every 10 mL/min/1.73m² reduction in glomerular filtration rate (GFR), the risk of stroke increases by 7% [5]. Dialysis patients also have an elevated risk of stroke with a much higher mortality [6, 7]. CKD and stroke have shared cardiovascular risk factors. Similarities exist between the brain and the kidney in terms of vascular anatomy, vasoregulatory and bidirectional humoral and non-humoral pathways [8]. Despite this, the increased risk of stroke is not fully explained by aggregation of these traditional risk factors within the CKD population [9]. CKD itself is therefore an independent risk factor for stroke in studies of the general population [9, 10].

The impact of a historical stroke and the development or progression of subsequent CKD has not previously been well characterised. The aims of this study were twofold. Firstly, to investigate the associations between a prior stroke and major cardiovascular and kidney disease outcomes, including non-fatal cardiovascular event (NFCVE), ESRD and death, in a large UK cohort of patients with ND-CKD. Secondly, to determine the impact of history of prior stroke on mortality for patients who were initiated on dialysis.

The study used data from the Salford Kidney Study (SKS), previously known as the Chronic Renal Insufficiency Standards Implementation Study (CRISIS), a longitudinal epidemiological cohort study of more than 3000 adults with all-cause ND-CKD recruited since October 2002 [11, 12]. Ethical approval was granted by the regional ethics committee (REC15/NW/0818). Inclusion criteria were patients 18 years or older, referred to a tertiary renal centre (catchment population 1.55million) with an eGFR < 60 mL/min/1.73m² and not requiring immediate renal replacement therapy. Demographic, comorbidity and laboratory data were recorded at baseline and annually. Mortality data were obtained by cross referencing with national mortality data and locally held death certification. Self-reported cerebrovascular and cardiovascular events and event dates were validated following review of clinical records, radiology reports, general practice records, clinical coding and outpatient clinic letters.

Inclusion criteria for the current analyses are summarised in Fig. 1. Data were analysed on the basis of whether the participant had suffered a stroke prior to recruitment or not. Transient ischaemic attacks (TIAs) were not included in the stroke group because the study set out to specifically ascertain the impact of stroke and not wider cerebrovascular disease on outcomes in CKD. TIA was also difficult to retrospectively prove prior to study commencement because the diagnosis is often clinical and up to 60% of patients referred to TIA clinics do not have a TIA [13, 14]. Hypertension was determined by antihypertensive prescription at recruitment or if patients had a coded diagnosis of hypertension in GP or hospital records. Blood pressure was the mean of 2 stable readings on the first study visit, using an automated sphygmomanometer with an appropriately sized cuff, after at least 5 min of seated rest. Heart failure was classified by the New York Heart Association classification. A composite outcome of NFCVE comprised myocardial infarction, coronary revascularization (including bypass grafting and non-fatal cardiac arrest), cerebrovascular events (stroke or TIA) and newly diagnosed peripheral vascular disease including amputation. Patients were followed from study recruitment until death, commencement of renal replacement therapy or eGFR < 10 mL/min/1.73m² using CKD-EPI formula [15]. For patients not reaching study end points, data were censored on the last hospital visit or on 2^nd March 2018. Date of renal replacement commencement and cardiovascular end points were confirmed by a study coordinator who was blinded to the baseline characteristics.

For the analysis of prevalent stroke at time of dialysis commencement, data were analysed using the date of first outpatient dialysis (haemodialysis) or first dialysis exchange in the community (peritoneal dialysis) as study start date. Stroke prior to dialysis commencement consisted of stroke events prior to recruitment and strokes events which occurred during study follow up. Patients were followed until death, transfer out of area or 2^nd March 2018.

In this prospective cohort study, we describe strong independent associations between stroke and the risk of major adverse clinical events in CKD. Patients who have experienced a stroke are at increased risk of mortality during the progression of CKD including at dialysis initiation. These risks were substantial and were only partially explained by adjustment of traditional CV risk factors.

Patients who suffered a stroke prior to recruitment had worse outcomes (death, ESRD and NFCVE) than those without stroke during follow up even after accounting for other known risk factors. This is a consistent with a previous Taiwanese population study (N = 100,353) which used coded definitions of cardiovascular events and CKD progression [18]. Our study provides additional clarity in a Caucasian population with the advantage of verification of cardiovascular events and inclusion of kidney function in the regression models.

In our study patients with a history of stroke were also less likely to commence dialysis despite having a higher rate of ESRD, reflecting that patients with previous stroke were more likely to have a non-dialysis care approach to their ESRD management. The evidence suggests that dialysis does not confer survival advantages in patients with a particularly high burden of comorbidity [19]. It is likely that those patients who had suffered a previous stroke but then commenced dialysis were those that made a more successful recovery. This may explain why renal transplantation rates were similar between those with and without prior stroke.

Patients with a prior stroke had a lower eGFR at recruitment (25.2 mL/min v 29.5 mL/min p < 0.01) but they were also on average 4 years older than patients without stroke. Cholesterol was lower in the prior stroke group (4.2 mmol/l v 4.5 mmol/l p < 0.01) most likely because of increased statin treatment (77.3% v 59.3% p < 0.01).

Despite good evidence that statin therapy can reduce the risk of major adverse ischaemic cardiovascular events in ND-CKD [20], and the role of statin therapy in secondary prevention of cerebrovascular disease, only 75% of prior ischaemic stroke patients were prescribed statin therapy. However, no data were available to indicate if patients had previously received statin therapy and subsequently stopped for a legitimate reason such as intolerance.

Only 70.1% of patients with an ischaemic stroke before study recruitment were prescribed antiplatelet agents, perhaps explained by different risk benefit analysis conclusions made by clinicians for secondary prevention of cerebrovascular disease in patients with CKD [21]. Inequalities of stroke care which occur in patients with concurrent renal disease may also have been a factor [22]. Data from the general population suggests that prescription of antiplatelets (97%) and lipid lowering therapy (95%) is very high in patients after ischaemic stroke [23].

Interaction analysis demonstrated a significant interaction between antiplatelets, stroke prior to recruitment and mortality. This effect was moderated but remained significant when excluding haemorrhagic, dual stroke pathology and undetermined stroke aetiologies. This finding could be demonstrating confounding by indication or it could mean that antiplatelets in CKD patients after a stroke predicts a worse outcome. This may explain why CKD patients with ischaemic stroke are not universally prescribed antiplatelets and supports Palmer et-al’s finding of uncertain benefits of antiplatelets in patients with CKD [21].

We found 8.3% of patients who commenced dialysis had suffered a previous stroke, consistent with other published data [7, 24] but lower than in the Dialysis Outcomes and Practice Patterns Study which reported a 13.7% prevalence of cerebrovascular disease. However, the latter included unverified cerebrovascular events including TIA and may therefore have over-estimated the reported prevalence [25].

The first dialysis modality choice was not proportionally different between the two groups. Two thirds of patients initially commenced haemodialysis and one third of patients commenced peritoneal dialysis irrespective of previous stroke. At present there is no clear guidance that patients with cerebrovascular disease should be offered a certain dialysis modality although recent studies suggest that peritoneal dialysis may be less harmful to the brain and reduce risk of stroke. Two longitudinal studies of prevalent dialysis patients have demonstrated that peritoneal dialysis may have less deleterious effects on patient’s cognitive function than HD [26, 27]. A Scottish national registry study also demonstrated length of time exposed to HD was independently associated with stroke whereas length of time exposed to peritoneal dialysis was not [28].

The prevalence of atrial fibrillation in the whole cohort at recruitment was 6.9% which is slightly lower than other published studies although similar methodology for atrial fibrillation data collection were used in both studies [29]. Patients did not undergo routine ECG testing so asymptomatic episodes of atrial fibrillation may have been missed.

Patients with a history of stroke who commenced dialysis had an increased risk of death after adjustments for other traditional cardiovascular risk factors. Other studies have also demonstrated that prior stroke is associated with higher mortality after dialysis commencement but without adjustment for confounding cardiovascular comorbidities [24]. In patients where cause of death was known, there was no significant difference in cardiovascular-specific death between the two groups who started dialysis. The unadjusted incidence of stroke after commencement of dialysis was 14.9 per 1000 patient years which is lower than in some published studies [6, 24] but similar to others [7]. This may be because cause of death was not available in the majority of patients, we did not include TIA as a stroke end-point and very few patients were from African American background who may have a higher risk of stroke independent of traditional risk factors [30].

It is encouraging that patients with a history of stroke and who were fit enough to commence dialysis had comparable chance of transplantation. Transplant rates and waiting times whilst undergoing dialysis were similar for both groups. Outcomes of transplantation in patients with a previous stroke are favourable and therefore clinicians should not be biased against transplant referral in patients with a prior stroke who are otherwise fit for transplantation [31].

The main strengths of this study are the large population size and the detailed characterisation of this CKD cohort, with thorough cardiovascular event assessment and long follow up duration.

A limitation of the study was the inability to validate the type of stroke in 50 patients at recruitment, 7 of whom commenced dialysis. Data on stroke severity at time of presentation or whether patients with ischaemic strokes received thrombolysis were not available. In addition, dialysis adequacy parameters were not included in regression models. Ischaemic and haemorrhagic stroke were combined and due to small numbers, analysis and outcomes were not split by the type of stroke. Furthermore, cause of death data was not available for all patients. Socioeconomic status was also not available in this dataset and is known to impact on CKD, vascular disease and mortality. Finally, this study was performed in a predominantly Caucasian population in a developed country. The South Asian population have a particularly high risk of stroke and cardiovascular disease which occurs at a younger age and is disproportionate to socio-economic or comorbid status [32]. The magnitude of the effect of stroke on patient and CKD outcomes in non-Caucasian CKD populations requires further study.

In this large prospective cohort of CKD patients, a diagnosis of stroke was independently associated with several major clinical outcomes including death, reaching ESRD and suffering another non-fatal cardiovascular event. These associations highlight the importance of the brain-kidney interactions in determining patient outcomes at critical timepoints along the CKD pathway.