We enrolled consecutive ischemic or hemorrhagic stroke patients who received LT or KT with or without simultaneous pancreas-kidney transplantation (SPKT) between January 2005 and December 2020 at Asan Medical Center, Seoul, Korea. Demographic features, comorbidities, laboratory findings, immunosuppressant use, stroke characteristics including etiologies (subtypes), antithrombotic agents at discharge, and 3-month mortality were obtained from our electronic medical records (EMR). Enrolled patients were dichotomized into two groups, LT and KT, according to their transplantation status. Patients with SPKT were classified into the KT group. The trial was approved by the independent Institutional Review Board (IRB) of Asan medical center, Korea, which waived the need for written consent due to the study's retrospective nature (IRB approval number: 2021-0475).

In our center, the care of transplantation recipients after discharge is performed by the transplantation center in conjunction with a coordinator, whom the patients may contact anytime if any medical condition requiring care occurs. Strokes were reported to the coordinator, and the patients were transferred to our hospital for further management, including post-transplantation care.

In this study, the diagnosis of stroke required both imaging evidence on magnetic resonance imaging (MRI) and the presence of relevant clinical symptoms, whether reported by the patient or observed during a neurologic examination. Acute ischemic lesions were evaluated based on diffusion-weighted imaging (DWI), and white matter changes were investigated using T2-weighted imaging (T2WI) or fluid-attenuated inversion recovery (FLAIR) sequence.

The etiology of ischemic stroke was classified according to the TOAST (Trial of org 10172 in acute stroke treatment) classification; ischemic strokes were classified as large artery atherosclerosis (LAA), small vessel occlusion (SVO), cardioembolism, and other determined and undetermined etiology (14). We diagnosed cardioembolism when a patient had more than moderate risk cardioembolic features and did not satisfy the diagnostic criteria of LAA and SVO. Patients were classified as having stroke of undetermined etiology if they did not have a positive finding to explain the cause of stroke (negative), had more than one possible cause (two or more), or did not complete the minimum evaluation for classification (incomplete).

In-hospital stroke was defined as an ischemic or hemorrhagic stroke occurring in a patient who was initially hospitalized for treatment for another condition (15, 16), including the post-surgical period. In the case of recurrent stroke, only a single earliest event was accounted for by a patient. We defined postoperative 3-month stroke as any ischemic or hemorrhagic infarctions that occurred within 90-days following the transplantation surgery. Among patients with ischemic stroke, the presence of hemorrhagic transformation was assessed only in those who underwent follow-up imaging (either MRI or CT) within 14 days after initial imaging. Multiple lesions and cortical lesion were also evaluated only in the case of ischemic stroke. We defined multiple lesions as discrete non-single hyperintense DWI lesions, regardless of whether they were within the same vascular territory or in different territories. A cortical lesion was defined as an abnormal DWI lesion involving the cortical gray matter of the cerebral or cerebellar hemispheres.

Imaging markers related to the ischemia burden were also investigated. Fazekas score was rated using fluid-attenuated inversion recovery (FLAIR) images, and the score ranged from 0 to 3, reflecting the burden of white matter change (17). In our study, we chose to focus on evaluating deep white matter change to assess the Fazekas score, as it is a more accurate indicator of small vessel disease burden (18) and represents overall white matter changes (19). Cerebral microbleeds were referred to small, rounded, or circular well-defined hypointense lesions within the brain parenchyma with clear margins ranging from 2 to 10 mm on gradient echo (GRE) images (20).

Continuous variables such as age and laboratory findings were analyzed by Mann–Whitney test, and categorical variables, including medical comorbidities, medications, characteristics of stroke, and 3-month mortality, were evaluated by chi-square or Fisher's exact test, as appropriate. Kaplan–Meier curve was used to evaluate the occurrence of stroke events in both groups. We used a two-sided p-value of < 0.05 to define statistical significance. Logistic regression analysis was performed to find factors related to mortality at three months, and variables with a p-value of same or < 0.05 were included in multivariate analysis. All statistical analyses were performed using SPSS version 26.0 (SPSS, Inc., Chicago, IL).

Between January 2005 and December 2020, we evaluated a total of 10,425 patients who underwent transplantation surgery at our hospital, including 5,950 LT recipients and 4,475 KT recipients. During this period, there were 105 (1.8%) and 58 (1.3%) post-transplantation stroke patients in the LT and KT groups including 3 SPKT patients, respectively. Two patients in the LT group who were diagnosed with both ischemic and hemorrhagic stroke simultaneously were included in both groups. The median age was 60.0 (interquartile rage: 54.0–65.5) years, and 73.9% were men.

In the LT group, the most common cause of transplantation was hepatocellular carcinoma (HCC) due to hepatitis virus (n = 41, 39.0%). Other causes were comprised of liver cirrhosis due to hepatitis virus (n = 28, 26.6%), liver cirrhosis related to alcohol consumption (n = 19, 18.1%), HCC related to alcohol consumption (n = 6, 5.7%), HCC with unknown cause (n = 2, 1.9%), and liver cirrhosis with unknown cause (n = 9, 8.6%). In the KT group, diabetes (n = 31, 53.4%) was the most frequent cause of transplantation, and ESRD of other causes (n = 11, 19.0%), hypertension (n = 10, 17.2%), IgA nephropathy (n = 4, 6.9%), and polycystic kidney disease (n = 2, 3.4%) followed.

Table 1 shows the detailed clinical characteristics of the patients who experienced strokes after LT and KT. the LT group had lower rates of vascular risk factors such as diabetes (35.2 vs. 67.2%, p < 0.01), hypertension (45.9 vs. 86.2%, p < 0.01), and coronary arterial disease (10.5 vs. 24.1%, p = 0.02) than in the KT group. The incidence of active cancer, defined as histologically or cytologically confirmed malignancy and diagnosed or received treatment within 6 months or progressive disease (21), was higher in the LT group (21.0 vs. 5.2%, p = 0.01). Laboratory studies at the time of stroke event showed a lower platelet count and a higher international normalized ratio (INR), activated partial thromboplastin time (aPTT), aspartate transaminase (AST) level, and alanine transferase (ALT) levels in the LT group than in the KT group. Conversely, total cholesterol and creatinine levels were higher in the KT group.

Table 2 shows the features of stroke in the LT and KT groups. Among the 105 recipients of the LT group, two of them experienced both ischemic and hemorrhagic strokes simultaneously and counted twice. The occurrence of strokes tends to happen earlier in the LT group than the KT group, as illustrated in Figure 1, but the difference did not reach statistical significance (median 274.0 days vs. 401.0 days; p = 0.11). On the other hand, the LT group had a higher incidence of postoperative 3-month stroke (43.9 vs. 27.6%, p = 0.04), In-hospital stroke (57.9 vs. 39.7%, p = 0.03), and hemorrhagic stroke (25.2 vs. 8.6%, p = 0.01) compared do the KT group.

The distribution of TOAST classification did not show a significant difference between LT and KT groups. In both the groups, undetermined etiology was the most common cause of stroke. More specifically, in the LT group, the most frequent cause of the stroke was undetermined etiology (n = 30, 37.5%), which consisted of in the order of negative etiology (n = 25), incomplete evaluation (n = 4), and 2 or more etiologies (n = 1). The second most common etiology in the LT group was SVO (n = 25, 31.3%), followed by cardioembolism (n = 10, 12.5%), LAA (n = 9, 11.3%), and other determined etiology (n = 6, 7.5%). In six other determined etiology patients, air embolism (n = 2), cervical artery dissection (n = 1), cancer-related stroke (n = 2), and coronary artery angiography-related stoke (n = 1) were the causes of stroke.

In the KT group, the undetermined etiology (n = 17, 32.1%) was the most frequent etiology as well, followed by SVO (n = 13, 24.5%) and cardioembolism (n = 13, 24.5%). The undetermined etiology comprised of 15 cases with negative etiology, 1 with 2 or more etiologies, and 1 with incomplete evaluation. One (1.9%) patient with other determined etiology was diagnosed with Moyamoya disease. Further evaluation of imaging features such as multiplicity, cortical involvement, and hemorrhagic transformation did not differ between the two groups. The presence of microbleeds and Fazekas score were also similar between the two groups. At discharge, a higher proportion of LT patients (44.9 vs. 25.9%, p = 0.02) did not receive antithrombotic agents.

The all-cause 3-month mortality was approximately 10% in the both groups (KT, 10.3%; LT, 10.3%; p > 0.99). Results of the multivariate logistic regression analysis (Table 3) showed in-hospital stroke (odds ratio [OR], 4.17; 95% confidence interval [CI], 1.07–16.30) and elevated C-reactive protein (OR, 1.10; 95% CI, 1.01–1.20) levels were related to all-cause mortality. After conducting a subgroup analysis, we found that in the LT group, C-reactive protein level was independently associated with an increased risk of 3-month mortality after the multivariable analysis, while no significant factors were identified in the KT group (Supplementary Tables 1, 2).