This large-scale retrospective observational study provides real-world findings regarding the risk of CVD following kidney transplantation. The study demonstrated that CVD risk was higher in the KTR group than in the control group and that KTRs with comorbid hypertension, hyperlipidemia, diabetes mellitus, chronic kidney disease, and depression were at further risk. Male sex and older age were risk factors for CVD, and this risk increased over time following transplantation. CBD risk was also higher in the KTR group than in the control group.

The risks of CVD and mortality are lower among KTRs than among patients receiving dialysis. Nevertheless, these risks are higher among KTRs than in the general population 19. KTRs have double the risk of cardiovascular mortality compared with the general population 20, 21. The high incidence of CVD after kidney transplantation is primarily due to the presence and accumulation of traditional risk factors both before and after the transplant 22.

Male and older-adult KTRs, especially those aged 51-60 years, have a higher risk of CVD. The incidence of CV remains high after transplantation. A study using survival model analysis identified the following as key predictors of cardiovascular events in KTRs: male sex, older age, previous CVD, pretransplant smoking, and posttransplant diabetes mellitus 23. These factors increase the risk of cardiovascular events 23. Age and sex are risk factors for vascular disease 24. CVD accounts for one-third of all deaths following transplantation, with individuals aged 50 years or older facing a significantly higher risk than the general population 9.

KTRs with comorbid hypertension, hyperlipidemia, diabetes mellitus, chronic kidney disease, and depression had a higher risk of CVD than did KTRs without these comorbidities. Traditional cardiovascular risk factors, such as hyperlipidemia, hypertension, and diabetes mellitus, are common in KTRs, partly due to the effects of immunosuppressive drugs. These factors contribute to adverse outcomes and increase the burden of CVD after transplantation 14, 25. Hypertension is a major risk factor for atherosclerotic CVD, which is the leading cause of premature death and a major factor in graft failure among transplant recipients 26. Although hypertension is a significant risk factor for renal graft survival, controlling hypertension alone does not seem to improve outcomes. Graft survival is more affected by the severity of graft dysfunction at the start of observation, regardless of blood pressure control 27. Dyslipidemia is common among KTRs, even when renal function remains normal or nearly normal 28. Dyslipidemia is an important risk factor for CVD 29. The prevalence of hyperlipidemia among KTRs has been estimated to reach up to 80% 30. Abnormal glucose metabolism significantly increases the risk of fatal and nonfatal cardiovascular events 31, with a threefold higher risk of cardiac death or nonfatal acute myocardial infarction compared with patients without diabetes 32. Patients with pretransplant diabetes mellitus (PreDM) had an increased risk of mortality from cardiovascular diseases compared to those without diabetes 33, 34. Another study also indicted that PreDM patients have the highest incidence of major adverse cardiovascular events and cardiac-related mortality following transplantation 35. Patients with PreDM experienced significantly lower survival rates, with up to a 50% higher risk of death while on the transplant waiting list and a 70% increased risk of CVD and all-cause mortality 36, 37. Chronic kidney disease increases the risk of death among KTRs, and KTRs with chronic kidney disease are more likely to require dialysis than are KTRs without chronic kidney disease 38. CVD is a significant cause of morbidity and mortality among patients with chronic kidney disease 21. Progressive renal dysfunction increases the risk of cardiovascular complications following transplantation 4. Chronic kidney disease increases the risk of adverse outcomes, with CVD being the leading cause of death in this population 39. Cardiovascular mortality increases as kidney function declines, even after adjusting for traditional risk factors, indicating that chronic kidney disease is an independent risk factor for CVD 40. In advanced chronic kidney disease stages (3b-4), 40%-45% of patients die from CVD rather than progressing to end-stage kidney disease requiring transplantation or dialysis 41. Depression and anxiety are consistently identified as the most prevalent psychiatric disorders among organ donors following donation 42. Anxiety and depression are associated with higher morbidity following kidney transplantation 43. A meta-analysis associated depression but not anxiety with an increased risk of posttransplant mortality 44. Despite progress in renal transplantation, depression is still a common and problematic comorbidity that remains largely overlooked. In this context, depression is associated with poorer outcomes, including reduced graft survival 45.

CVD risk increased over time following kidney transplantation. Among the four follow-up periods we assessed, the 5-year follow-up period had the highest CVD risk, followed by the 3-year follow-up period. CVD has become a major contributor to graft loss, especially after the first year following transplantation 4. We applied competing risk methodology and found that the cumulative incidence of cardiovascular events was 5.0% at 1 year after transplantation, 8.1% at 5 years, and 11.9% at 10 years 23. The cumulative incidence of posttransplant myocardial infarction was 4.3% following transplantation, 4.1%-4.5% at 6 months, 5.6% at 12 months, and 11.1% at 36 months 46. The cumulative incidence of coronary heart disease following transplantation was 3.1% at 1 year, 5.2% at 3 years, and 7.6% at 5 years 47.

Our study indicates that the risk of CBD was higher in KTRs compared to non-transplant patients during the 5-year follow-up period. In contrast, the 6-month follow-up period was associated with a lower CBD risk (aHR 0.53, 95% CI: 0.28-0.99). However, the lower limit of the confidence interval is close to negligible. The incidence of posttransplantation stroke in KTRs varies from 1.1% to 8.0% 11-15. Single-center studies have demonstrated the adverse mortality implications of posttransplantation cerebrovascular disease events in KTRs 13, 48. The cumulative 3-year incidence of new-onset cerebrovascular events after kidney transplantation was 6.8%. Among patients on the waiting list, this incidence was 11.8%, and among those with graft loss, this was 11.2% 14. Transplantation reduced the risk of cerebrovascular events by 34% compared with remaining on the waiting list, and the risk of cerebrovascular events increased by more than 150% after graft failure 14. Cerebrovascular events are associated with negative implications for mortality 14. Kidney function within the first year after transplantation has consistently been recognized as an important factor that affects longer-term graft survival 49, 50. KTRs experience a gradual decline in glomerular filtration rate over time, which is strongly associated with donor age and aortic stiffness after the first year following transplantation 51. A study has shown evidence of the involvement of kidney disease in both the early and later phases of cerebrovascular atherosclerosis and cerebral small vessel disease 52. Kidney dysfunction was linked to an increased risk of stroke, regardless of the etiological subtype 53. The incidence of stroke in KTRs was 5% in the first year following transplantation and 9.4% in the second year 15. This study revealed that the incidence of stroke was relatively lower in the early stages after transplantation but increased in the later stages. Our research shows that the risk of CBD was higher in KTRs than in non-transplant patients over the 5-year follow-up period. On the other hand, the 6-month follow-up period was linked to a lower risk of CBD. This may be associated with initial improvement in kidney function in the early post-transplant period, followed by a gradual decline over time. However, further well-designed controlled prospective studies are needed to confirm whether CBD risk continues to increase over time following kidney transplantation.

CVD risk was higher in the KTR group than in the control group, and this risk increased over time. CBD risk was also higher in the KTR group. Clinicians must comprehensively understand the risks of CVD and CBD following kidney transplantation to minimize complications.

The present study has several strengths. First, it used a nationwide, population-based sample, selecting patients from the entire Taiwanese population and following them over a long period. This approach provided a large, representative sample with high statistical value and minimized selection bias. Second, we investigated the risks of CVD and CBD in KTRs at different time points after transplantation (i.e., 6 months and 1, 3, and 5 years).

This study has some limitations. First, selective reporting bias and data errors may have resulted from the study's retrospective cohort design. Second, the study used the NHIRD, which is a secondary database. Because the NHIRD lacks laboratory details and medical examination data, we were unable to evaluate diagnostic criteria. Third, the NHIRD lacks data on smoking habits, alcohol consumption, body mass index, personal medical history, physical activity, and dietary habits, all of which are linked to CVD and CBD risk. Fourth, all diagnoses in this study were based on ICD-9-CM or ICD-10-CM classifications. Taiwan's Bureau of National Health Insurance enhances diagnostic accuracy by randomly reviewing charts and conducting patient interviews, ensuring that analyses using NHIRD data are valid and accurate. Nonetheless, we acknowledge that some confounding variables may not have been controlled for in this study. Last, some comorbidities, such as metabolic syndrome, obesity, and obstructive sleep apnea, are associated with the occurrence of CVD and CBD. However, due to the limited number of patients with these conditions, their inclusion could lead to overdispersion in the regression analyses. Therefore, they were not incorporated into this study. This study focused on the incidence of CVD and CBD after kidney transplantation, without further analysis of the underlying reasons for transplantation. While end-stage renal disease (ESRD) is the most common indication, other conditions, such as congenital anomalies, genetic disorders, or rare kidney diseases, may also lead to kidney transplantation. Different transplantation indications could potentially influence post-transplant CVD and CBD risk. Future studies should consider incorporating the causes of transplantation to better understand their impact on cardiovascular and cerebrovascular outcomes.