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Takafumi Mizuno, Takao Hoshino, Kentaro Ishizuka, Sono Toi, Ayako Nishimura, Shuntaro Takahashi. Sho Wako and Kazuo Kitagawa

Department of Neurology, Tokyo Women's Medical University Hospital

Aims: We aimed to determine the characteristics and vascular outcomes of stroke in renal transplant (RT)recipients and compare them with those in patients on hemodialysis (HD) and those with no renal replacement therapy (RRT).

Methods: In this prospective observational study,717patients (mean age.70.8 years; male,60.5%) with acute ischemic stroke within one week of onset were consecutively enrolled and followed for one year. The patients were classified into three groups:(1)living donor RT recipients(n=27);(2) patients on maintenance HD before the index stroke (n=39); and (3) those with no history of RRT(n-651). The primary outcome was a composite of major adverse cardiovascular events (MACE).

Results: Diabetic nephropathy was the most common reason for RRT in both RT and HD patients. RT patients were more likely to have an embolic stroke of undetermined source (33.3%)than others, whereas HD patients more often had cardioembolism(51.3%). No difference was observed in the MACE risk between the patients in RIand non-RRTgroups (annual rate,11.3% ys,13.1%; log-rank P-0.82: hazard ratio [95%confidence interval],0.92 [0.29-2.98]). In contrast, HD patients had a greater risk of MACE than those with no RRT(annual rate,28.2% vs.13.1%;log-rank P=0.019;hazard ratio [95% confidence interval],2.24[1.16-4.3]). Conclusions: The underlying etiologies of stroke differed in RT and HD patients. The one-year risk of MACE for stroke patients who had received an RT was lower than that for patients undergoing HD and comparable with that of patients with no RRT.

Keywords: Embolic stroke of undetermined source, End-stage kidney disease,Hemodialysis,

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Introduction

Renal replacement therapy (RRT), including renal transplant (RT), and hemodialysis (HD), remarkably increase the life expectancy of patients with end-stage kidney disease. 2). However, RRT patients have a substantial risk of cerebral- and cardiovascular events, which should be a major consideration for life-long management after RRT According to data from the United States Renal Data Systems3), the prevalence of stroke and coronary artery disease was 26%, and 9%, respectively, in patients with a functioning RT. For patients undergoing HD, the prevalence was even higher;44% and 17% had experienced a stroke and coronary events, respectively. Furthermore, the leading cause of death is vascular accidents for both RT and HD patients3. Hence, there is the need to develop a better approach to prevent and treat vascular diseases in patients undergoing RRT

To date, stroke in HD patients has been well studied in terms of clinical aspects and prognosis4-8 On the other hand, limited data are available on stroke in RT recipients. Given the recent increase in the number of patients with renal failure receiving RT3, a better understanding of stroke after RT is of utmost importance. Living donor RT is much more common than cadaveric RT in Japan, and it accounts for approximately 85.9 % of all RT cases, whereas cadaveric RT is more common in the majority of countries). In the present study, we aimed to characterize stroke in living donor RT recipients based on robust clinical, laboratory, and imaging data and determine their one-year prognosis compared with those receiving HD as well as those with no history of RRT.

Methods

Study Design and Patients

The Tokyo Women's Medical University (TWMU) Stroke Registry is a single-center prospective observational study, in which patients with acute ischemic stroke or transient ischemic attack hospitalized at our center within one week of onset were consecutively enrolled. The study adhered to the ethical principles of the 1975 Declaration of Helsinki, as well as the Ethical Guidelines for Epidemiological Research by the Japanese government and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. The study protocol was approved by the ethics committee of Tokyo Women's Medical University Hospital (approval no.2955-R2). Written informed consent was obtained from all the patients.

Between December 2013 and September 2019, 806 patients were enrolled in the study. After excluding 7 patients who met the exclusion criteria (e.g., stroke mimics as final diagnosis or more than one week after stroke onset) and 82 patients with the transient ischemic attack, the data of 717 patients with acute ischemic stroke were included for the present analysis(Supplementary Fig.1).

All the cases of stroke were diagnosed by board-certified stroke neurologists based on neurological and radiological findings. Upon admission, the neurological symptoms were assessed using the National Institutes of Health Stroke Scale(NIHSS)score. The patient data collected included demographic data, clinical symptoms during the qualifying event, medical history, medications, investigations (including blood tests, brain, and cerebral artery imaging,24-hour Holter electrocardiogram, and ultrasonic echocardiography), management (medical treatment, revascularization procedure, and surgery), and the occurrence of clinical events after the qualifying event using a structured case report form. Renal Disease

We identified patients who had a history of living donor RTor were undergoing maintenance HD before the index stroke (RT and HD groups, respectively). Information on primary kidney diseases that necessitated RRT was obtained from previous medical records. None of the patients in our cohort received cadaveric RT. The estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease formula with the Japanese coefficient; chronic kidney disease (CKD)was defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m².

Evaluation of Atherosclerotic Disease

The intracranial arteries were examined using time-of-flight magnetic resonance angiography (n=686) and/or computed tomography angiography (n=146). The narrowest diameter of each stenosed vessel was measured and divided by the diameter of the normal vessel proximal to the lesion or distal to the lesion if the proximal artery was diseased. Significant intracranial artery stenosis was defined as >50% stenosis or occlusion.

Extracranial carotid atherosclerosis was evaluated using ultrasonography (n=675) and/or computed tomography angiography (n=81)and/or time-of-flight magnetic resonance angiography(n=66). We defined significant extracranial artery stenosis as the presence of atherosclerotic stenosis of >50% or occasion according to the European Carotid Surgery Trial criteria9.

Aortic atherosclerosis was evaluated using transesophageal echocardiography (n=226). Mobile plaques were diagnosed as mobile components that swung on their peduncles. An ulcerative plaque was diagnosed as a discrete indentation of the luminal surface of the plaque with a base width, as well as a maximum depth, of at least 2 mm. Complex aortic atheroma was defined as any plaque with a thickness of ≥4 mm or ulceration or mobile components10.

Ischemic Stroke Subtly

The etiologies of ischemic stroke were classified into atherothrombosis, cardioembolism, small-vessel disease, other determining causes, and undetermined causes, according to the Trial of Org 10172 in Acute Stroke Treatment(TOAST) classification). Strokes of undetermined causes were further divided into an embolic stroke of undetermined source(ESUS), stroke with coexisting etiologies, and incomplete 

investigations. ESUS was diagnosed based on the proposed criteria by the cryptogenic stroke/ESUS international working group(i.e., stroke detected by computed tomography or magnetic resonance imaging that is not lacunar; absence of extracranial or intracranial atherosclerosis causing  50% luminal stenosis in arteries supplying the area of ischemia; no major-risk cardioembolic source of embolism or no other specific cause of stroke identified)12).

Follow-up and Outcomes

Patients visited our center after 3 months and thereafter every 1 year for 3 years after enrollment. This study reports one-year outcomes. At follow-up visits, findings from physical examinations, treatments, any occurrence of clinical events, and the modified Rankin Scale (MRS)scores were recorded. If the patient could not be reached for follow-up, a relative or caregiver was interviewed via telephone. The primary outcome was a composite of major adverse cardiovascular events (MACE), including nonfatal stroke (ischemic or hemorrhagic), nonfatal acute coronary syndrome, major peripheral artery disease, and vascular death. Vascular death was defined as fatal acute coronary artery disease, fatal stroke, and other cardiovascular deaths. Secondary outcomes included stroke subtype and all-cause mortality. Stroke-related functional outcomes were assessed using the Mrs score at one year. A poor functional outcome was defined as an mRS score of 23.

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Statistical Analysis

Quantitative variables were expressed as mean (standard deviation)for normally distributed data or median (interquartile range). The qualitative variables were presented as frequencies (percentages). The patients were classified into the RT, HD, and non-RRT groups. We further divided the non-RRT patients into those with and without CKD. The comparisons of the groups were performed using the t-test, Mann-Whitney U test, one-way analysis of variance, or Kruskal-Wallis test for quantitative variables and x2 test for qualitative variables, as appropriate. The event rates were estimated using the Kaplan-Meier method, and the inter-group differences were assessed using the log-rank test. Cox proportional hazard regression models were used to calculate the age- and sex-adjusted hazard ratios and 95%confidence intervals for the patients with RT and HD, in comparison with those without RRT. The data for the patients with no information at one year were censored at the time of the last available follow-up. For a given outcome, the patients who died of causes other than the outcome were censored at the time of death. Events that occurred after one year of follow-up were not included in the current analysis. To identify the predictors of poor functional outcomes, we performed multiple logistic regression analyses with adjustments for age, sex, RRT modality, and admission NIHSS score. For all the analyses, statistical significance was set at P<0.05.

Results

Of the 717 patients (mean age,70.8 years; male, 60.5%),27 patients(3.8%)had received living donor RT and 39 patients (5.4 %) were undergoing maintenance HD; the remaining 651 patients(90.8 %)had no history of RRT. The median duration from RT surgery to stroke onset was 33 months (interquartile range,7-150 months)in the RT group. The median duration from HD initiation to stroke onset was 124 months(interquartile range,63-157 months) in the HD patients. Diabetic nephropathy was the most frequent reason for RRT in both the RT and HD groups (Table 1). The usage rates of

immunosuppressive agents in patients with RT are shown in Supplementary Table 1. Immunosuppressive regimens were not changed after the index stroke. Table 2 shows the baseline characteristics of the patients. Patients in the RT group were younger, and those in the HD group more often had chronic heart failure and peripheral artery disease than the others. There were no differences in the prevalence of atherosclerotic diseases in the intra- and extracranial arteries and aortas among the 3 groups. The low-density lipoprotein concentrations were lower, and the homocysteine concentrations were higher, in the RT and HD groups than in the non-RRT group.The brain natriuretic peptide level was highest in the HD group. The comparisons of the baseline characteristics of the patients with the RT, HD, no RRT with CKD, and no RRT without CKD groups are shown in Supplementary Table 2. Regarding the etiologic subtype (Fig.1 and Supplementary Fig.2), ESUS was more frequent in the RT patients than in the others. As shown in Supplementary Table 3, there were no relationships between specific immunosuppressive agents with the development of ESUS. On the other hand, cardioembolism was more frequent in HD patients. In the HD group, unfractionated heparin and low-molecular-weight heparin were used in 32

and 6 patients, respectively, for anticoagulation of the extracorporeal circuit. There were no significant associations of the type of anticoagulant for HD with a specific subtype of ischemic stroke.

The data on medication use at discharge and surgery are presented in Supplementary Table4. The usage rates of antiplatelet and anticoagulant agents were 74.1% and 32.1% in the RT group and 59.0%and 46.5% in the HD group, respectively. Among the RT and HD patients with 74.1% and 87.2%prevalence of hypertension, ≥ 1 antihypertensive agents were used in 61.5% and 82.1%, respectively at discharge.

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One-Year Event Risk

Among the 717 patients, 96 had at least one vascular event within one year, giving an event rate of 13.4%(95% confidence interval,11.1 %-16.1%). As shown in Fig.2 and Table 3, patients in the HD group had a significantly higher risk of MACE than those in the non-RRT group. No differences were observed between the MACE risks of the patients in the RT and non-RRT groups. These results were consistent when patients with no RRT history were further divided according to the presence or absence of CKD(Supplementary Fig.3). There was no difference in the risk of all-cause mortality across the three groups.

There were 3 and 5 patients who experienced a recurrent stroke in the RT and HD groups, respectively. Subtypes of the index and recurrent strokes were coincident, except for 1 patient in the HD group who had atherothrombosis at first and then developed cardioembolism during follow-up (Supplementary Table 5). Supplementary Table 6 shows comparisons of the 1-year MACE risk between each immunosuppressive agent users and non-users among the RT patients. Cyclosporine and mizoribine tended to raise the risk of MACE with no statistical differences, whereas tacrolimus and mycophenolate mofetil were associated with a lower risk. In the HD group,32(84.2%)and 6(15.8%)patients used unfractionated heparin and low-molecular-weight heparin during the HD procedure, respectively. As shown in Supplementary Table 7, the event rates of MACE and ischemic stroke were not significantly different between the anticoagulant drugs.

One-Year Functional Prognosis

Fig.3 shows the distributions of the Mrs scores at one-year follow-up. The percentages of patients with poor functional outcomes tended to be lower in the RT group, although the difference was not statistically significant. The inter-group difference was significant when the patients with no RRT were subdivided into those with CKD and those without CKD(Supplementary Fig.4). The multivariable analysis showed that RT or HD was not independently associated with poor functional prognosis at one year; age and NIHSS were independent determinants of disability (Table4).

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