KoreaN cohort study for Outcome in patients With Kidney Transplantation (KNOW-KT) study: an overview focused on cardiovascular outcomes from the Korean kidney transplant cohort

Article information

Korean J Nephrol. 2025;.j.krcp.25.140

Publication date (electronic) : 2025 December 16

doi : https://doi.org/10.23876/j.krcp.25.140

Jung-Hwa Ryu¹, Myung-Gyu Kim², Kyu Ha Huh³, Hee-Yeon Jung⁴, Jae Berm Park⁵, Seungyeup Han⁶, Kyung Pyo Kang⁷, Wookyung Chung⁸, Jaeseok Yang^,9, on behalf of the KNOW-KT Study Group^*

¹Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Republic of Korea

²Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea

³Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea

⁴Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea

⁵Department of Surgery, Sungkyunkwan University Samsung Medical Center, Seoul, Republic of Korea

⁶Department of Internal Medicine, Keimyung University Dongsan Medical Center, Daegu, Republic of Korea

⁷Department of Internal Medicine, Jeonbuk National University Hospital, Jeonju, Republic of Korea

⁸Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea

⁹Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea

Correspondence: Jaeseok Yang Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. E-mail: JCYJS@yuhs.ac

*The complete list of the KNOW-KT Study Group can be found in the Acknowledgments section.

Received 2025 May 14; Revised 2025 November 3; Accepted 2025 November 3.

Abstract

Introduction

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

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.

Table 1.

Baseline demographic and clinical characteristics of recipients

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).

Figure 1.

Baseline characteristics of the recipients in KoreaN cohort study for Outcome in patients With Kidney Transplantation (KNOW-KT) Phase I cohort.

(A) Primary causes of renal disease before kidney transplantation (KT). Among the causes, diabetes mellitus (DM) was the most frequent cause of renal disease. (B) Almost all of the transplantations were performed in the first transplantation. (C) Pretransplant renal replacement therapy was performed in 79%, and HD accounted for the largest proportion at 65%. Preemptive KT was performed in 21%. (D) The median dialysis vintage was 12 months (0–365 months). (E) The portion of living donor KT (LDKT) was 82% of the entire population. Among the LDKT, living related donors were more prevalent compared to living unrelated donors.

ADPKD, autosomal dominant polycystic kidney disease; DDKT, deceased donor kidney transplantation; GN, glomerulonephritis; HD, hemodialysis; HTN, hypertension; PD, peritoneal dialysis.

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.

Table 2.

Baseline demographic and clinical characteristics of donors

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.

Figure 2.

Patient survival of kidney transplant recipients.

(A) Overall patient survival during follow-up. (B) Patient survival based on donor types (living donor kidney transplantation [LDKT] vs. deceased donor kidney transplantation [DDKT]).

Table 3.

Risk factors for patient death and cardiovascular events by the multivariate Cox proportional hazard method

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).

Figure 3.

Cardiovascular disease (CVD) event-free survival of kidney transplant recipients.

(A) Overall CVD-free survival. (B) CVD-free survival based on donor types (living donor kidney transplantation [LDKT] vs. deceased donor kidney transplantation [DDKT]).

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].

Figure 4.

Cardiovascular (CV) events according to OPG, CACS, AACS, changes in WHR ratio, or BMI of transplant recipients.

(A) Kaplan-Meier (KM) survival curves for posttransplant CV events based on the OPG levels (p-value, comparison between the high and low OPG groups using the log-rank test). (B) Prediction of hazard ratios for CV events using the Cox proportional hazard model according to the continuous values of serum OPG levels with a restricted cubic spline curve. (C) KM curves for incidence of CV outcomes according to CACS groups (CACS = 0; 0 < CACS ≤ 100, CACS > 100). (D) KM curves for incidence of CV outcomes according to AACS groups (0, 1–4, and >4). (E) Effects of changes in WHR every year on CV events. (F) Relative hazard ratio of new-onset CV disease according to changes in WHR in model A and B. (G) Associations between BMI and CV events after kidney transplantation by multivariate analysis, adjusted for age, sex, diabetes, hypertension, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, and CV disease.

AACS, abdominal aortic calcification score; BMI, body mass index; CACS, coronary artery calcium score; CI, confidence interval; CVD, cardiovascular disease; NA, not available; OPG, osteoprotegerin; OR, odds ratio; WHR, waist-to-hip ratio.

Panels A and B were adapted from Jeon et al. (Transplantation 2024;108:1239–1248) [12]; Panels C and D were adapted from Ha et al. (Kidney Dis (Basel) 2024;10:249–261) [10] according to the Creative Commons License; Panels E and F were adapted from Gwon et al. (Sci Rep 2021;11:783) [13] according to the Creative Commons License; panel G was adapted from Kim et al. (Transplant Proc 2017;49:1038–1042) [14] with original copyright holder’s permission.

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].

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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