Objectives: Stroke is a major cause of mortality in the general population but data regarding stroke-related hospitalization or mortality after a kidney transplant is limited. We determined risk for stroke-related episodes after a kidney transplant in a population-based cohort study of 19 103 kidney allograft recipients in England between 2001 and 2012.

Materials and Methods: The incidence of stroke-related events after a kidney transplant with pretransplant history of stroke, the incidence of stroke-related hospitalization or death among all kidney allograft recipients after a kidney transplant, and risk factors for stroke-related mortality after a kidney transplant were examined. Data were obtained from hospital episode statistics (an administrative data warehouse that contains admissions to all National Health Service hospitals in England) and is linked to the Office for National Statistics, which collects information on all registered deaths in England.

Results: There were 782 nonfatal stroke-related hospitalizations and 113 stroke-related deaths (5.4% of total deaths) after a kidney transplant (median follow-up 4.4 y after a kidney transplant). Risk for all-cause mortality was higher for those recipients with, compared to those without, a history of stroke (21.5% vs 10.8%; P < .001). However, risk for stroke-related mortality after a kidney transplant was no different. Kidney allograft recipients with nonfatal stroke episodes after a transplant were at a higher risk for all-cause and stroke-related mortality. In a Cox regression model, pretransplant history of stroke was an independent risk factor for all-cause mortality, but not stroke-related mortality, while posttransplant hospitalization with nonfatal stroke was a risk factor for both.

Conclusions: Fatal and nonfatal stroke-related events are common among kidney allograft recipients. Further research is warranted to allow better risk stratification and facilitate clinical trials for risk attenuation of stroke after a kidney transplant.

Key words : Cerebrovascular accident, Death, Transplant

Introduction

Stroke, or cerebrovascular accidents, is one of the leading causes of mortality in the world, estimated to be the second leading cause of global death by the World Health Organization.¹ In 2010, the global absolute numbers of individuals developing their first stroke, surviving stroke, or having a stroke-related death were 16.9 million, 33.0 million, and 5.9 million, with 69% of events occurring in individuals aged greater than 65 years.² In addition, stroke-related disability represents a significant health burden, with disability-adjusted life years lost an estimated 102 million globally in 2010.² Although age-standardized rates of stroke-related mortality are decreasing worldwide,^2,3 absolute numbers are increasing and they represent a major public health burden.

In the context of transplant, the effect of stroke-related morbidity or mortality after a transplant is unclear because of a lack of published data. Oliveras and colleagues observed a 10-year incidence rate of stroke at 8.0% in their single-center analysis of 403 patients, with nearly a 50% mortality risk within 3 months after the stroke.⁴ Aull-Watschinger and colleagues observed 54 strokes (and 10 transient ischemic attacks) among 1633 recipients transplanted between 1995 and 2005 (incidence, 3.9%), of which 19 were fatal.⁵ De Mattos and colleagues observed 48 stroke-related events (39 strokes, 6 transient ischemic attacks, and 3 carotid endarterectomies) in a cohort of 922 kidney allograft recipients who received a transplant between 1993 and 1998 (incidence, 5.2%), with 17 stroke-related deaths.⁶ Lentine and associates have published the only population-based cohort analysis examining mortality from stroke after a kidney transplant.⁷ Using data from the United States Renal Data System, they found a 3-year incidence of de novo stroke at 6.8% (lower than estimates on the waiting list or after graft loss). To our knowledge, no other study has been conducted at a population level to evaluate the effect of stroke-related events (fatal and nonfatal) in the context of kidney transplant; this represents a major gap in the literature.

We undertook a population-based cohort study of all kidney allograft recipients who underwent a transplant in England between 2001 and 2012 to investigate: the incidence of stroke-related events after kidney transplant with a pretransplant history of stroke; the incidence of stroke-related hospitalization or mortality among all kidney allograft recipients after a transplant in a population-based cohort; and the risk factors for stroke-related mortality after a kidney transplant.

Materials and Methods

Study design
This was a retrospective observational cohort study performed on prospectively registered national data sets. This study included all kidney transplant procedures performed at any kidney transplant center in England (adult and pediatric) between April 2001 and March 2012. Combined organ transplants (kidney with another organ) were excluded from the analysis (n = 1255). During this time, 19 688 kidney transplant procedures were recorded (635 recipients had repeat transplant performed during the 11-year period, but were only factored into the survival analysis). We excluded 585 procedures because of incomplete data in relation to demographic information (ie, age, gender, or socioeconomic deprivation), leaving a final cohort of 19 103 kidney allograft recipients for analysis.

Data sources
Data were obtained from Hospital Episode Statistics (HES), an administrative data warehouse containing admissions to all National Health Service hospitals in England.⁸ We extracted data using codes on procedural classifications (Office of Population Censuses and Surveys Classification of Interventions and Procedures, 4th revision [OPCS-4])⁹ and medical classifications (World Health Organization Inter-national Classification of Disease, 10th revision [ICD-10]).¹⁰ Kidney transplant procedure OPCS-4 codes used were M01, M05, M08, and M09. Regarding mortality data, HES is limited by only capturing hospital deaths. Therefore, we obtained complete mortality data by cross-referencing our study cohort with mortality data from the Office for National Statistics (ONS), which collects information on all registered deaths in England.

This study did not require formal institutional review board approval because of the pseudo-anonymized nature of the data retrieved. The Health and Social Care Information Centre (hscic), uses a special HES ID code, linking the data and avoiding patient identifiable codes. This study was carried out in accordance with the principles of the Declaration of Helsinki. This analysis is part of the Kidney Allograft Recipients in the United Kingdom observational study, which is registered with a clinical trials registry (NCT01798524).

Study variables
Patient demographic data extracted from each kidney transplant procedure performed in England at the time of transplant included age, gender, donor type (living vs deceased), ethnicity (white, black, South Asian, other, and unknown), allograft failure, medical comorbidities (ie, stroke, acute myocardial infarct, congestive heart failure, peripheral vascular disease, pulmonary disease, connective tissue disorder, peptic ulcer, cancer, liver disease, and diabetes mellitus), and socioeconomic deprivation (based upon Index of Multiple Deprivation 2010).¹¹ Data regarding posttransplant hospitalization for stroke (hemorrhagic or thrombotic) were extracted from the HES. Data regarding allograft failure were defined using a surrogate marker in the absence of specific obtainable data (return to dialysis for ≥ 10 dialysis sessions beyond 90 days after a kidney transplant). These data were obtainable only from April 2006 onwards (11 961 kidney transplant procedures performed during this time in England) and constitute supportive analysis for the Cox regression models.

Data quality
We adhered to the principles of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement and have reported this article in accordance with the recommended guidance.¹² Additionally, we checked the data accuracy from the HES database regarding transplant activity by corroborating the HES data with the UK Transplant National Transplant database (where all transplant activity must be mandatorily reported).

Classification of death
All deaths were classified into system-based categories. Two authors (DF, JC) converted all causes of death from ONS data from string to numeric data, with a third author independently verifying the data (AS). Any discrepancy on classification was resolved by discussion. Causes of death were classified under 12 different categories (eg, stroke, cardiovascular, infection, malignancy).

Statistical methods
Primary outcomes were fatal and nonfatal stroke-related episodes after a kidney transplant. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 20.0, IBM Corporation, Armonk, NY, USA). Normality of data was assessed using the Kolmogorov-Smirnov tests. Descriptive statistics were used to estimate frequencies. Categorical variables are presented as number (%) and continuous variables as mean (± standard deviation) or median (± interquartile range) dependent upon normality of distribution. Difference between groups was assessed with chi-square or 2-sided Fisher exact test for categorical variables, and the t test or the Mann-Whitney U test to compare continuous variables. P values < .05 and .001 in the statistical analysis were considered significant.

The Cox proportional hazards regression model and Kaplan-Meier estimation were used for survival analyses. The proportional assumption was checked for each variable and the entire model; and for the main analysis, the proportional assumption is true for all variables except cancer. Variables included in the model were age, gender, donor type (ie, living vs deceased), allograft failure, socioeconomic depri-vation, ethnicity (as classified by ONS), year of transplant, nonfatal stroke-related hospitalization after a transplant, and selected medical comorbidities (eg, history of myocardial infarction, peripheral vascular disease, stroke, congestive cardiac failure pulmonary disease, liver disease, peptic ulcer, previous cancer, and diabetes). Posttransplant events were included as time-dependent covariates.

Assuming the data were randomly missing, we performed listwise deletion and excluded the missing values from the analysis. Other missing data (eg, ethnicity) were adjusted as “dummy variables” in the models as required.

Results

A total of 19 688 kidney transplant procedures in England were recorded in the HES data for adult (n = 18 499) and pediatric (n = 1189) kidney allograft recipients between April 2001 and March 2012. Data were corroborated with the UK National Transplant database for the same time, with 98.6% concordance between both data sets. Excluding those with missing demographic data (n = 585), we had a cohort of 19 103 for further analysis (104 154 patient-years for entire study cohort).

The median age for the whole cohort was 45 years (interquartile range, 34-55 y). The gender of the study population included 11 673 males (61.1%) and 7430 females (38.9%). Ethnic breakdown of the study cohort included white (13 695; 71.7%), black or black British (934; 4.9%), Asian or Asian British (1704; 8.9%), Chinese (81; 0.4%), mixed (166; 0.9%), other ethnic group (350; 1.8%), and unknown (2173; 11.4%). Socioeconomic deprivation quintiles were as follows (from most to least-deprived): one (22.0%), two (22.0%), three (19.7%), four (18.3%), and five (18.0%). Living-donor transplant occurred in 6262 (32.8%) of all kidney transplant procedures reported. Diabetes mellitus classification was the most common medical comorbidity recorded in 2968 (15.5%) of all kidney allograft recipients.

Stroke-related mortality after kidney transplant
By cross-referencing both HES and ONS databases, we identified 113 stroke-related deaths (0.6% of overall study cohort and 5.4% of total deaths) that occurred after a kidney transplant with median follow-up 4.4 years (interquartile range, 2.2-7.3 y; 104 154 patient-years). This equates to a crude mortality rate of 108 deaths per 100 000 person-years. The 3 most common causes of death after a kidney transplant were cardiovascular events (424 deaths per 100 000 person-years), infection (417 deaths per 100 000 person-years), and cancer (361 deaths per 100 000 person-years). Table 1 illustrates differences in baseline demographics between kidney allograft recipients who died from a stroke compared with all other causes of mortality.

Median time to stroke-related death was 3.2 years after a kidney transplant (interquartile range, 1.6-6.4 y). Of these stroke-related deaths 26 (23.0%) occurred within the first year after a kidney transplant. There was a single case of stroke-related mortality in a kidney allograft recipient with known stroke and this occurred 90 days after a transplant.

Nonfatal stroke hospitalization posttransplant
The incidence of hospitalization after a kidney transplant secondary to nonfatal stroke was explored. Of the total population cohort, 782 kidney allograft recipients were hospitalized with any type of stroke. There were 192 hemorrhagic and 622 thrombotic nonfatal events, with 32 cases of patients having both events. Patients with pretransplant history of stroke had double the risk of nonfatal stroke events posttransplant compared with those with no prior stroke history (2.8% vs 1.4%; P = .003).

Kidney allograft recipients hospitalized with nonfatal stroke posttransplant, compared with those with no episodes, were subsequently at a higher risk for all-cause mortality (29.2% vs 10.1%; P < .001) and stroke-related mortality (10.7% vs 0.2%; P < .001) at median follow-up. This was the case for nonfatal hemorrhagic and thrombotic strokes. Compared with no posttransplant stroke events, admission with nonfatal hemorrhagic stroke was associated with increased risk of subsequent all-cause (10.6% vs 39.7%; P < .001) and stroke-related mortality (0.3% vs 24.7%; P < .001). Admission with nonfatal thrombotic stroke was associated with increased risk of subsequent all-cause compared with no posttransplant stroke events (10.4% vs 25.9%; P < .001) and stroke-related mortality (0.4% vs 6.9%; P < .001).

Stroke and mortality risk among recipients with history of pretransplant stroke
Stroke-related comorbidity was recorded for 284 kidney allograft recipients at the time of transplant, representing 1.5% of the total cohort. Table 2 highlights significant differences between kidney allograft recipients with, versus those without, a preexisting stroke in relation to these baseline differences.

Kidney allograft recipients with pretransplant history of stroke were at increased risk of nonfatal stroke events posttransplant compared with those without pretransplant strokes (7.7% vs 4.0%; P = .004). Kidney allograft recipients with pretransplant history of stroke demonstrated a higher risk for all-cause mortality after kidney transplant compared with those without previous stroke (21.5% vs 10.8%; P < .001). Figure 1 illustrates the difference in unadjusted all-cause mortality risk between recipients with, versus those without, pretransplant stroke as a Kaplan-Meier plot. Risk for all-cause mortality within the first year after a kidney transplant was higher for those recipients with, compared with those without, a pretransplant history of stroke (9.2% vs 2.9%; P < .001).

Looking at specific causes of death, Figure 2 shows a pie chart highlighting the causes of all 61 deaths that occurred after a kidney transplant in the 284 recipients with pretransplant stroke history. Death from a cardiovascular event and cancer were the 2 leading causes of death. Compared with other kidney allograft recipients, recipients with history of pretransplant stroke were more likely to die from cardiovascular events (2.3% vs 4.9%; P = .007) or cancer (1.9% vs 3.9%; P = .026), but not from infection (2.3% vs 2.8%; P = .319). Compared with other kidney allograft recipients, recipients with a history of pretransplant stroke had a lower risk of death from stroke after a kidney transplant, but this did not achieve statistical significance (5.5% vs 1.6%; P = .146).

Regarding malignancy-related mortality after a kidney transplant, there was no significant difference in type of cancer, but a trend toward more lung cancer deaths was noted in kidney allograft recipients with pretransplant history of stroke versus nonstroke (27.3% vs 17.3%; P = .075).

Multivariable Cox regression analysis
Cox regression analyses were performed to identify independent predictors of mortality after kidney transplant and confirmed the incidence of a previous history of stroke at the time of transplant, or that after a transplant hospitalization with nonfatal stroke were independent risk factors for all-cause mortality after a transplant. Other significant results from our multivariable model are shown in Table 3. Adding allograft failure into a supportive Cox regression model (incorporating kidney allograft recipients from 2006 onwards) retained a similar result with regard to the importance of nonfatal strokes (both pre- and posttransplant) for subsequent all-cause mortality.

Regarding independent risk factors for stroke-related mortality, the following parameters were significant on Cox regression analysis: age, receipt of a deceased (vs living) donor kidney, and post-transplant hospitalization with nonfatal stroke (see Table 4). A pretransplant history of stroke was not significantly associated with stroke-related mortality.

Discussion

In this study, we have demonstrated that 284 (1.5%) of 19 103 kidney allograft recipients transplanted in England between 2001 and 2012 had a pretransplant history of a stroke. These pretransplant stroke patients have an increased risk for all-cause, but not stroke-related, mortality after a kidney transplant (primarily driven by increased cardiovascular and malignancy deaths). In total, there were 782 nonfatal stroke-related events (4.1%) and 113 fatal stroke-related events (0.6%) after a kidney transplant, with a crude mortality rate of 108 deaths per 100 000 person-years. Risk for stroke-related death was higher with increased age and posttransplant hospitalization with nonfatal stroke, although recipients of living-donor kidneys had reduced stroke-related mortality risk. This population-based cohort analysis of stroke-related hospitalization and mortality after a kidney transplant, in the context of universal health coverage, provides contemporary data to guide clinical practice and counsel patients.

The low prevalence of known stroke before a kidney transplant in our cohort underestimates the true prevalence of stroke-related morbidity and mortality in the general population. The prevalence of stroke in the United Kingdom is 2.4% for men and 2.2% for women, with a 20% fatality.¹³ The incidence of stroke in the general population is 178 and 139 per 100 000 for men and women in the United Kingdom.14 This becomes increased in the context of advanced renal impairment compared with the general population.¹⁴ Therefore, it is important to acknowledge that our pretransplant stroke patient cohort under investigation in this analysis has a selective bias toward recipients who survived nonfatal strokes with acceptable degree of subsequent morbidity.

Previous population-based analysis by Lentine and colleagues⁷ underscores the important observation that a functioning kidney allograft lowers the risk of stroke in patients with end-stage kidney disease (compared to those on the waiting list for a kidney allograft). In a retrospective analysis of Medicare beneficiaries in the United States, the authors found the 3-year incidence of de novo stroke events was 6.8% posttransplant, 11.8% for subjects on the waiting list, and 11.2% in subjects after graft loss. The analyses also show that smoking is a potentially reversible correlate of stroke events after a transplant and women had an increased risk. It is important that transplant candidates deemed at high risk for stroke after a transplant should not be overlooked for a kidney allograft (as a working kidney allograft will reduce the risk of stroke), and a careful risk-versus-benefit analysis should be conducted for each patient. This is similar to data regarding reduction of cardiac events after a kidney transplant versus patients on a wait list.¹⁵

Long-term risk of recurrent stroke after a first-ever nonfatal stroke in the general population has been estimated at 30% actuarial risk by 5 years (9-fold increased risk vs nonstroke general population), with highest risk within the first year.¹⁶ The decreased trend for stroke mortality after kidney transplant in our study cohort of stroke patients may reflect aggressive work up pretransplant to determine medical suitability and attenuation of cardiometabolic risk factors. However, this cannot be the complete explanation, as cardiovascular-related mortality remained elevated in our cohort of recipients with a previous stroke.

In the general population, long-term mortality risk among stroke patients is predominantly related to cardiometabolic disease. Brønnum-Hansen and colleagues¹⁷ found the 2 most common causes of long-term mortality after a stroke in the general population were cardiovascular (22.7%) and cerebrovascular (32.1%). Rutten-Jacobs and colleagues found similar findings in a prospective cohort analysis entitled The Follow-Up of Transient Ischemic Attack and Stroke Patients and Un-elucidated Risk Factor Evaluation (FUTURE) study.¹⁸ Long-term mortality was analyzed after either a transient ischemic attack, ischemic stroke, or hemorrhagic stroke in adults aged 18 through 50 years admitted to a single Dutch center between January 1, 1980, and November 1, 2010. The 20-year mortality among 959 subjects recruited in the study cohort was 20.0% (n = 192), with the 3 most common causes of death cardiovascular (26.2%), cerebro­vascular (19.3%), and malignancy (23.4%).

The bidirectional relation between stroke and malignancy is well documented in the general population,¹⁹ and there is emerging data regarding similar interplay after a kidney transplant. A pretransplant history of stroke has previously been identified as one of the strongest independent risk factors for malignancy-related mortality after a kidney transplant.²⁰ This may reflect shared risk factors, such as smoking, which we were unable to account for in our analysis. Evidence to support this hypothesis in this study was the trend toward more lung cancer deaths in the kidney allograft cohort with pretransplant strokes, acknowledging smoking to be one the strongest risk factors for both.²¹ This present finding replicates the data found in the general population that Bang and colleagues found lung cancer to be the most common primary cancer type in patients with strokes versus those without strokes (29.2% vs 11.5%; P < .001).²²

Risk for all-cause and stroke-related mortality was higher in our cohort of patients with nonfatal hemorrhagic versus thrombotic strokes. This mirrors data from Abedini and colleagues that demonstrates a higher mortality in the context of hemorrhagic strokes in a posthoc analysis of the ALERT study.²³ In this study, the risk for hemorrhagic stroke was increased in patients with diabetes mellitus, poly­cystic kidney disease, and hypertension. Therefore, such patients require adequate counseling of long-term risks and attenuation of risk factors, such as glycemic control and hypertension, to reduce subsequent mortality risk.

The reduced risk for stroke-related death with living-kidney donor transplant is important, especially in the context of the increasing age of kidney transplant candidates. Previous work from our group demonstrated all-cause mortality risk for recipients aged 70 and over in a population cohort in the United Kingdom was 32.2% at median 4.4 years after a transplant, with risk increasing to 41.2% with concomitant pretransplant history of stroke incidence.²⁴ However, recipients aged ≥ 70 years, who received living-donor kidneys reduced their risk of all-cause mortality to 20.7%. Therefore, actively exploring the possibility of living-donor kidney transplant would be beneficial for high-risk patients such as elderly candidates with or without pre­transplant history of stroke.

There are limitations to our analysis that must be acknowledged. We were unable to differentiate between strokes and transient ischemic attacks on pretransplant coding, which could have allowed stratification of the risk of death after a transplant. We also did not have any information regarding stroke-related disability, an important cause of long-term morbidity among stroke survivors. Other limitations include the absence of unmeasured or incompletely measured covariates that are not accounted for in the analysis. It is unlikely that statistics can ever fully adjust for all confounding factors in a cohort study, and this is a limitation inherent to the very nature of observational analyses. The absence of detailed information in relation to the study cohort at baseline is a limitation of the retrospective nature of this cohort study. For example, absence of data on immunosuppression and cardio­vascular risk factors (eg, smoking, hypertension, hyperlipidemia, and family history) affects the risk of stroke-related mortality. In addition, the lack of information on dialysis histories and wait list timing are important variables, notable for their absence in our analysis, as they are important confounders on our mortality endpoints. Finally, registry data have well-documented limitations^25-27 that lead to inherent problems with such analyses, and acknowledgement of these shortcomings is essential in the correct interpretation of our results.

In conclusion, we have demonstrated stroke is the cause of 1 in 20 deaths after a kidney transplant and associated with identifiable risk factors. Pre­transplant history of stroke is associated with increased risk of all-cause but not stroke-related mortality after a kidney transplant. Posttransplant hospitalization with nonfatal stroke is a strong risk factor for both all-cause and stroke-related mortality. A greater understanding of stroke-related incidence and/or mortality risk after a kidney transplant is required to allow transplant clinicians to adequately counsel patients. Additionally, the possibility of tailoring modifiable risk factors (eg, immuno­suppression) appropriately in this setting should be explored, but this will require evaluation in targeted clinical trials.

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