;on behalf of the KNOW-KT Study GroupIntroduction
End-stage renal disease (ESRD) is a leading cause of death worldwide [1,2] and is rapidly increasing the burden on global health and healthcare. According to the 2017 Global Burden of Disease Study, the age-standardized death rate due to chronic kidney disease (CKD) increased from 11.6 to 15.9 per 100,000 individuals between 1990 and 2017, resulting in 1•2 million deaths in 2017 [3].
Kidney transplantation (KT) is the most appropriate treatment for patients with ESRD [4], as it prolongs patient survival and improves quality of life [5,6]. Usually, short-term outcomes of the KT population have been remarkably improved because of developments in organ procurement and surgical techniques, advanced immunosuppressive regimens targeting acute early rejection, and prophylactic antibiotic or antiviral therapies. However, the long-term prognosis is not guaranteed because the patients already have a lot of predisposing comorbidities, and these primary combined diseases are not resolved even after transplantation. Moreover, it is unclear whether immunosuppressant management is safe. During the entire posttransplant period, individuals are prone to multiple complications such as cardiovascular disease (CVD), diabetes mellitus (DM), malignancies, infectious diseases, mineral bone disease, fracture, and psychological complications [7,8]. Among these, CVD outcome is common and essential because KT recipients already have CKD-related CVD risks before transplantation.
The KoreaN cohort study for Outcomes in patients With Kidney Transplantation (KNOW-KT) was launched to follow the long-term prognosis and document the risk factors of the adverse outcomes. From 2012 to 2016, KNOW-KT recruited 1,115 adult kidney transplant recipients from eight university-affiliated transplant centers in Korea. The KNOW-KT study is expected to provide high-level evidence on the epidemiologic, clinical, and immunologic factors for diverse outcomes and transplant-associated complications. Moreover, because this study included many immunologically incompatible transplant cases and was designed to analyze precise parameters for cardiovascular (CV) outcomes, it is expected to provide significant and inspiring information on long-term outcomes and prognosis during the posttransplant period. To create a more robust database and consider the dropouts in Phase I, we launched a Phase II study in 2022 to enroll 300 recipient-donor pairs.
As of November 2024, the KNOW-KT Study Group has published 23 articles in peer-reviewed international journals. We aimed to provide a basic design and summary of the meaningful findings, focusing on all-cause mortality and CV outcomes from the KNOW-KT study.
Methods
Study population
In Phase I of the KNOW-KT study, 1,115 participants who received KT were recruited from eight university-affiliated tertiary care hospitals throughout Korea from 2012 to 2016. Participants in the Phase II study were recruited between 2022 and 2024. As of December 2024, 300 KT recipient-donor pairs were registered, all living kidney transplants. Recipients of both living- (LDKT) and deceased-donor KT (DDKT) and donors of LDKTs were enrolled after informed consent was obtained. The participants were all ethnic Koreans (recipients and donors) over 18 years old. The patients who were ≤18 years old and those undergoing simultaneous multiorgan transplantation and en-bloc KT were excluded.
The individual Institutional Review Boards of the participating hospitals approved this cohort study (No. 4-2014-0290), which was performed in accordance with the Declaration of Helsinki and the Declaration of Istanbul. The registration and tracking statuses of Phases I and II are shown as flow diagrams in Supplementary Fig. 1 (available online).
Study design and data collection
The KNOW-KT was a prospective observational cohort study, and the detailed design and methodology have been previously described [8]. Briefly, the medical data of recipients and donors were prospectively collected. After enrollment, the recipients were followed up annually or until death, graft failure, or dropout. These data included epidemiological factors, comorbid conditions, health-related quality of life, desensitization, laboratory data from baseline to follow-up, immunologic factors, information about the types and doses of immunosuppressants, CV function and calcification measurement, echocardiography, pulse-wave velocity (PWV), ankle-brachial index, abdominal aortic calcification score (AACS), coronary computed tomography (CT), allograft-related outcomes including rejection, biopsy, and patient outcomes including posttransplant complications, CVD, infections, and malignancy. Donor information was collected at the time of enrollment. Transplant donor data included demographics, comorbidities, and laboratory data at baseline. This study recently added information about vaccination and coronavirus disease 19 infection.
Nephrologists, general surgeons, epidemiologists, laboratory medicine specialists, and biostatisticians participated in the study. The protocol summary was registered at ClinicalTrials.gov (accession number: NCT02042963). The CKD stages were defined according to the estimated glomerular filtration rate calculated using the 2009 CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine-based equation [9]. Serum creatinine level was measured using an IDMS (isotope-dilution mass spectrometry)-traceable method.
Sample collection
Blood samples for DNA analysis were collected from recipients and donors before transplantation. Blood samples for RNA analysis were collected from recipients 1, 3, and 5 years after transplantation. Baseline serum samples were collected from the recipients before, at 1, 3, and 5 years after transplantation. After sample collection and processing according to the manufacturer’s protocol, the blood samples were stored by an external company (LabGenomics).
Outcomes
The primary endpoints of this study were all-cause mortality and CV outcomes. All-cause mortality was categorized into CVD, infection, malignancy, liver disease, sudden cardiac death, accident, suicide, others, and unknowns according to the causes of death. Participants who dropped out of the study were traced for this information with the help of the National Health Insurance Service and the Korean Statistical Information Service.
CV outcomes included myocardial infarction, coronary revascularization, stroke, and new-onset or aggravation of congestive heart failure.
Statistical analysis
In the KNOW-KT study, the statistical analysis results are reported once a year after the data-cleaning procedure. Continuous variables were represented as mean ± standard deviation values or medians with interquartile ranges (IQLs). Student t test or analysis of variance was used to compare continuous variables, and the chi-square test or Fisher exact test was used to compare categorical variables. All-cause mortality and CV events were estimated using the Kaplan-Meier method and the log-rank test. Significant variables in the univariate Cox regression analyses (p < 0.05) and variables known to be clinically important in previous studies were entered into the multivariate Cox proportional hazards model. These factors were considered independent risk factors for respective outcomes.
Results
Baseline characteristics
There were 1,115 registered kidney transplants initially in the Phase I cohort; after the exclusion, 1,080 recipients were analyzed (Table 1; Supplementary Fig. 1, available online). Among them, 885 were LDKT, and 195 were DDKT. The mean age of the recipients was 45.8 ± 11.6 years, and the LDKT group was younger than the DDKT group (45.2 ± 11.7 years vs. 48.8 ± 10.5 years, respectively). Among all registered recipients, 62.4% were male, and the proportion of males was similar between the LDKT and DDKT groups.
Among recipients, 838 (77.6%) underwent dialysis before KT. Glomerular disease was the most prevalent cause of chronic renal disease (Fig. 1A). The first KT was the most common, and second transplantation occurred in 6% of cases (Fig. 1B). Among the patients who underwent pretransplant renal replacement therapy, 705 (65.3%) underwent hemodialysis and 133 (12.3%) underwent peritoneal dialysis (Fig. 1C). Pretransplant dialysis, including both hemodialysis and peritoneal dialysis, was less frequent in the LDKT group than in the DDKT group. Hemodialysis was performed in 62.9% (n = 557) vs. 75.9% (n = 148), and peritoneal dialysis in 9.9% (n = 88) vs. 23.1% (n = 45), respectively. Preemptive KT was performed in 221 patients (25.0%) who underwent LDKT. The median duration of dialysis before KT was 5 months (IQL, 1.0–36.0 months); 3.0 months (IQL, 1.0–13.0 months) in LDKTs and 69.5 months (IQL, 39.3–96.0 months) in DDKTs (Fig. 1D).
Living donors constituted 81.9% of all donors. Among living donors, 60.6% were living-related donors, of whom 42.2% were siblings and 30.4% were offspring. Among living unrelated donors, 97.1% were spouses (Fig. 1E).
Three hundred recipient-donor pairs were enrolled in the Phase II cohort, with three dropouts (Table 2). Two participants died; therefore, 295 recipients are currently being followed up.
All-cause mortality
During a median follow-up of 9.8 years, 50 deaths occurred after KT. The survival curve showed a gradual decline over time (Fig. 2A). There were no significant differences between LDKT and DDKT (Fig. 2B). The risk factors for death included older recipient age (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.03–1.11; p < 0.001), history of DM (HR, 2.80; 95% CI, 1.48–5.31; p = 0.002), and high creatinine levels at discharge (HR, 1.45; 95% CI, 1.08–1.93; p = 0.01) (Table 3). The most common cause of death was infection (32.5%), followed by CV death, including sudden cardiac death (13.9%) and malignancy (11.6%), after the exclusion of unknown causes of death (Supplementary Fig. 1, available online). Although CV mortality was not high, a high pretransplant coronary artery calcium score (CACS) was a risk factor for overall mortality (HR, 2.74; 95% CI, 1.27–5.92) [10]. Furthermore, according to a previous analysis from the same KNOW-KT cohort [11], early statin use was associated with a 62% reduction in overall mortality.
Cardiovascular outcomes
Seventy-two patients developed CV events over 11 years, which was not higher than that in the general population. Compared to DDKT, LDKT showed a trend of a lower incidence of CV events without statistical significance (Fig. 3A). Risk factors for CV events included recipient age (HR, 1.06; 95% CI, 1.03–1.09; p < 0.001), DM (HR, 2.97; 95% CI, 1.77–4.96; p < 0.001), donor creatinine level (HR, 1.39; 95% CI, 1.09–1.77; p = 0.008), and high low-density lipoprotein (LDL) cholesterol (HR, 1.01; 95% CI, 1.00–1.02; p = 0.03) (Table 3).
Researchers in the KNOW-KT Study Group conducted studies to identify the potential risk factors associated with CV events. Patients with high serum osteoprotegerin (OPG) concentrations before transplantation had a three times higher incidence of CV events after transplantation (Fig. 4A, B) [12]. When CACS was categorized into three groups (0, >0 to ≤100, and >100), the higher CACS before transplantation was associated with a higher incidence of CV events after transplantation (HR, 2.74; 95% CI, 1.27–5.92) (Fig. 4C). AACS before transplantation also faced higher CV outcomes after transplantation (HR, 2.38; 95% CI, 1.16–4.88) (Fig. 4D) [10].
CV events development increased with an increase in waist-to-hip ratio (WHR) after transplantation, and a higher WHR was associated with new-onset CV events (Fig. 4E, F) [13]. Body mass index (BMI) changes after transplantation varied among recipients. When BMI was categorized as low (<23 kg/m2) and high (≥23 kg/m2), recipients with persistently high BMI—defined as ≥23 kg/m2 both before and 1 year after transplantation—had a significantly higher risk of CV events. Persistently high BMI before and after transplantation was associated with an approximately eightfold higher incidence of CV events compared with low BMI (Fig. 4G) [14].
Cardiovascular function markers after kidney transplantation
The average blood pressure (BP) was 124/78 mmHg 1 year after transplantation, and 46.3% of the patients took antihypertensive medication. From year 2 onwards, the average BP gradually increased from 125/79 mmHg to 130/78 mmHg, which was well controlled. Approximately one-third of patients (31.9%–36.3%) used a single antihypertensive medication to maintain normal BP within a normal range. Patients taking two types of antihypertensive medications were 22.8% to 23.5% of the cohort. The prescription rate of the renin-angiotensin system inhibitors was 13.9% in the first year and increased to more than 30% by the 11th year. However, over time, after transplantation, the number of antihypertensive medications increased. The types and proportions of antihypertensive agents used each year, as well as the number of agents prescribed, were summarized in the Supplementary Table 1 (available online).
CACS was assessed before and 5 years after transplantation and was not recovered but progressed after transplantation (Supplementary Fig. 2A, available online). High-scored baseline CACSs positively correlated with high scores at 5 years after transplantation (γ2 = 0.835) (Supplementary Fig. 2B, available online) [10]. AACS scores increased from before, 3 years, and 5 years after transplantation (Supplementary Fig. 2C, available online), and baseline AACSs correlated with 5-year scores after transplantation (γ2 = 0.526) (Supplementary Fig. 2D, available online).
Brachial-ankle PWV was measured before transplantation and at 3- and 5-year follow-ups. The mean PWV before transplantation was 1,553.2 ± 302.2 cm/sec on the right side and 1,538.9 ± 311.7 cm/sec on the left side. The average PWV at 3 years significantly decreased to 1,476.1 ± 283.7 cm/sec on the right and 1,456.6 ± 322.6 cm/sec on the left. However, they increased again at 5 years: 1,508.4 ± 312.7 cm/sec on the right and 1,496.6 ± 327.7 cm/sec on the left, despite still lower values than before transplantation (Supplementary Fig. 2E, available online). A comparison of vascular calcification and stiffness based on pretransplant OPG levels showed that both CACS and AACS were significantly higher in the high OPG group than in the low OPG group. Although both CACS and AACS increased over time, regardless of the OPG level, the rate of increase was steeper in the high OPG group. Pretransplant PWV was higher in the high OPG group than in the low OPG group. These values decreased at the 3-year follow-up compared to baseline in both groups; however, they later increased in both groups, maintaining intergroup differences (Supplementary Fig. 2F–H, available online) [12]. Baseline sclerostin levels, which were categorized into three tertile groups, showed a similar trend. In an investigation of changes in AACS and PWV based on pretransplant sclerostin tertiles, these two values at baseline were highest in the third tertile sclerostin group. AACS increased significantly over time in tertiles 2 and 3 compared with those in tertile 1. The PWV at baseline decreased in all three groups at the 3-year follow-up; however, it increased prominently in the third tertile group of sclerostin levels (Supplementary Fig. 2I, J, available online) [15].
KoreaN cohort study for Outcome in patients With Kidney Transplantation (KNOW-KT) Phase II
KNOW-KT recently launched Phase II enrollment for 2022–2024. This study was designed to create a cohort group of approximately 1,000 participants across Phases I and 2, considering the dropout rate in the Phase I study. It consists of a registry centered on living donors with known donor information. The inclusion criteria were the same as those used for the Phase I cohort, and nutritional information was complemented in this study.
Discussion
We investigated the current Korean kidney transplant status and observed posttransplant CV outcomes. Furthermore, we analyzed the risk factors for CV complications, particularly after LDKT. The KNOW-KT cohort had pretransplant donor information and comprehensive posttransplant outcomes, which are necessary to evaluate the long-term prognosis in causative observations. The baseline data of organ donors and recipients and the posttransplant data of the recipients were recorded annually [8]. The KNOW-KT reports have been published annually since 2013. This study summarizes the baseline characteristics, long-term patient survival, CV outcomes, and risk factors for each outcome of the KNOW-KT cohort.
In 2014, the Korean Organ Transplantation Registry (KOTRY), the prospective nationwide organ transplant registry, initiated and reported the short-term outcomes of the kidney transplant cohort in 2022 [16,17]. Although KOTRY involves a large population of transplants and a nationally representative cohort, it has inherent limitations regarding registry data. The KNOW-KT study features a more organized and complementary database that provides results related to CV assessment during the posttransplant period. In this cohort study, the CV event was planned as an outcome variable, and related prognostic indicators were proactively tested and tracked prospectively. Baseline and follow-up echocardiography, coronary CT, PWV, and 25-(OH)vitamin D measurements serve as cornerstone data for determining the cause-and-effect relationship in CV outcomes. In collaboration with KOTRY, KNOW-KT offers comprehensive information on Korean KT.
Over 10 years after transplantation, 50 deaths occurred, and the most common cause of death was infection, not CV events. In the KOTRY data with 5-year follow-up after transplantation, the most common cause of death was also infection. Because many infectious diseases occur in the early phase of KT and the cumulative incidence of infection increases, posttransplant preventive management from infection is essential. Time-related causes of death emerged as more significant factors, and a recent study emphasized that clinicians should focus on preventing death from infectious diseases and complications via surveillance in the early posttransplant [18]. Since 1990, all-cause mortality has progressively decreased with advancements in transplant medicine and surgical techniques, with a relatively greater reduction in CV deaths. However, infection-associated mortality in the early phase occupies a significant portion of early posttransplant death.
In this study, CVD-related mortality was not high. However, CV risk factors and management are closely associated with all-cause mortality. The overall mortality rate was reduced by 62% in a patient group that received statins early, suggesting that earlier management of atherosclerosis after transplantation can have long-term survival benefits [11]. Another study analyzed 58,264 kidney transplant patients, showing that administering statins reduced overall mortality by 5% [19]. This finding suggests that dyslipidemia management in transplant patients can have a positive effect on long-term survival, which may be helpful in the treatment guidelines for statin use in transplant patients. Baseline vascular calcification was associated with long-term survival, and patients with higher baseline CACS showed a lower survival rate during 10-year follow-up [10]. This cohort measured CACS and AACS, known risk factors for CV events, using coronary CT and lumbar spine radiography at baseline. The CACS was reevaluated 5 years after transplantation, and arterial calcification progressed during 5 years after transplantation [10]. High-scoring CACS and AACS before transplantation showed a positive correlation with high scores 5 years after transplantation, indicating that vascular calcification progressed after KT. Patients with a higher baseline CACS showed an even faster progression of allograft dysfunction [10]. Blood sclerostin concentration is related to vascular calcification, and a higher baseline sclerostin concentration is significantly associated with higher AACS and PWV posttransplantation [15]. So, serum sclerostin is expected to be used as a biomarker to predict vascular calcification after validation [15]. Even after resolving CKD-associated mineral bone disease after transplantation, arterial calcification continues to progress at a slower rate than that in dialysis patients [20]. Higher vascular calcification may explain the higher CV mortality in the KT population than in the general population [21]. Overall, pretransplant CV risk management is essential to prevent posttransplant CV events and premature mortality; early intervention for vascular health in patients with CKD is inevitable. The prevention of non-progressing vascular calcification is essential, and discovering biomarkers to predict the worsening of vascular calcification earlier is a future research task.
The incidence of CV events over 11 years was 6.9%, which did not exceed that observed in the general population and was lower than previously reported rates in KT recipients. Compared to DDKT, LDKT showed a trend toward a lower incidence of CV events, although the difference was not statistically significant. Major adverse CV events, including stroke, occurred in 82 patients (7.6%). The incidence of CV events in KT recipients has been reported as approximately 32% [22] and 3.5% to 5% per year. In a previous Korean study, the cumulative incidence of CV events after transplantation increased by 2.4% at 5 years, 5.4% at 10 years, and 11.4% at 12 years [23]. A similar pattern is expected in further follow-up of our cohort. This relatively low incidence may be attributed to the high proportion of LDKT recipients, the shorter dialysis vintage, and the considerable number of preemptive transplants, as well as an effective posttransplant care system that includes infection prevention and intensive medication monitoring during the early posttransplant period. Furthermore, early statin use was associated with better CV outcomes in this population. In addition, glomerulonephritis (GN) was the predominant cause of ESRD in this cohort, whereas DM and hypertension are the leading causes in most Western countries [24]. In Korea and several other Asian countries, GN remains one of the leading causes of ESRD, and has even been reported to surpass DM as a cause of kidney failure in certain periods [25,26]. This epidemiologic distinction likely reflects the relatively younger age and lower metabolic burden of Korean transplant recipients. Previous studies have demonstrated that patients with GN as the cause of ESRD have lower CV morbidity and mortality compared with those with diabetic nephropathy [27,28]. Accordingly, the predominance of GN in our cohort may partly explain the relatively low CV event rate and mortality observed in this study. Although KT provides superior survival benefits compared with long-term dialysis, the risk of CV mortality remains approximately two to five times higher in transplant recipients than in the general population [29,30]. Extended follow-up may further clarify the long-term CV risk among LDKT recipients compared with healthy individuals.
Risk factors for CV events included recipient age, pretransplant DM, donor creatinine level, and high LDL cholesterol level. DM is a known risk factor for CV events, and patients with DM should receive considerable management after KT. LDL cholesterol increases more with the use of immunosuppressants. Therefore, early intervention for hyperlipidemia could reduce the risk of CV events in KT patients, and statin treatment can decrease CV risk. Although early statin use was not associated with CV outcomes in our study, statin use in KT patients is associated with a lower risk of CV events and better patient survival without significant side effects [31]. Because there is no evidence of the harmful effects of statin therapy in the KT population, the CV protective effect of early or long-term statin use will be assessed in an expanded study. Other studies showed that a high CACS or AACS before transplantation and a significant increase in the WHR have been associated with a higher CV risk after transplantation [10,13]. Increased changes in BMI, from low to high and persistently high BMI, are associated with a higher risk of CV events. Persistently high BMI before and after transplantation showed eight times higher incidence of CV risk than the low BMI groups [14]. These findings suggest that active efforts are needed to prevent vascular calcification in patients with CKD, to preserve vascular health before transplantation, and to manage posttransplant metabolic disorders. Most participants in this cohort received LDKT, and more than 20% of patients had human leukocyte antigen-incompatible and ABO-incompatible transplants that required more potent immunosuppressants. So, these patients are at a high risk of metabolic abnormalities due to immunosuppressant-associated toxicities. Controlling metabolic complications is a key aspect of posttransplant management.
BP after transplantation influences CV outcomes. Well-controlled BP around 130/80 mmHg 1 year after transplantation gradually increased after 2 years, and the number of antihypertensive medications increased. Posttransplant hypertension is prevalent in 50%–80% of patients and deteriorates with CV outcomes [32]. Systolic BP >140 mmHg at 1 year after transplantation and an increasing systolic BP trajectory even within the normal range are associated with long-term graft dysfunction [33]. Over time after transplantation, the number of antihypertensive medications increases, indicating that polypharmacy is often necessary to manage hypertension, and this could influence the outcomes.
Brachial-ankle PWV is an indicator of vascular stiffness and a reliable predictor of CV risk and mortality, closely correlated with aging, hypertension, and degree of atherosclerosis [34,35]. The mean PWV was higher than the general population before transplantation and significantly improved after 3 years. However, these values increased again at 5 years, despite still having lower values than those before transplantation. A lower PWV is associated with better CV outcomes, and the absence of PWV worsening in the late posttransplant phase is associated with a lower CV risk [36]. Therefore, studies are needed on the relationship between posttransplant improvement or worsening of PWV at different points and the prevalence of CV events, as well as the relationship between various drugs, hypertension, worsening of existing diseases, and the increase in PWV over time after transplantation. Overall, CVD-related mortality increases with longer follow-up, and there is a need to analyze the potential risk factors for functioning graft status.
Our study had several limitations. Firstly, this observational cohort study lacked detailed information for all variables and outcomes. However, this well-organized design and data collection of the KNOW-KT cohort allowed for a more detailed analysis of the epidemiological factors, laboratory data, allograft outcomes, and patient outcomes compared with previous data.
Secondly, potential confounding factors cannot be controlled entirely in this observational study. Finally, CV risk assessments like CACS and PWV are followed up even 5 years after transplantation, and longer-term changes cannot be considered in this study.
Despite these limitations, the KNOW-KT study represents a significant advancement in the field of KT research, offering a comprehensive overview of both the baseline characteristics and long-term outcomes of kidney transplant recipients in South Korea. This cohort study provides valuable insights into long-term outcomes and prognostic factors in transplant recipients. Through comprehensive data, this cohort delivers pivotal insights into transplant recipients’ prognostic determinants and long-term trajectories, with particular emphasis on LDKT. By tracking participants over an extended period exceeding 15 years and incorporating analyses of nutritional markers and vaccination efficacy, this study extended its scope to comparative analyses involving the general population and individuals with CKD. These efforts aimed at establishing a Korean paradigm for clinical guidelines for transplant patient care. Furthermore, by comparing these findings with cohorts from other countries, we can systematically develop ways to improve survival rates and enhance the health status of recipients.
In conclusion, KNOW-KT is a longitudinal research project that is well-suited for understanding the long-term prognoses related to KT. This study lays the foundation for future research on KT, improves transplantation protocols, and ultimately enhances CV outcomes, pretransplant health control, and the health of kidney transplant recipients worldwide.
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