, Introduction
Kidney transplantation (KT) has become the gold standard treatment for patients with end-stage kidney disease, significantly improving survival and quality of life [1]. However, long-term immunosuppressive therapy to prevent graft rejection post-KT is associated with an increased risk of malignancy [2–5]. With the advancements in immunosuppressive regimens and evolving clinical practices including cancer screening before transplantation, contemporary data on cancer risk among kidney transplant recipients (KTRs) remain to be clarified [1]. Additionally, there is a growing need for real-world evidence that accounts for the diverse clinical profiles of KTRs, particularly regarding underlying comorbidities and transplant-related suppression of immunological surveillance of cancer.
Previous population-based nationwide cohort studies have primarily compared KTRs and the general populations without appropriate matching [4,6,7]. Furthermore, most studies have not incorporated differences related to underlying comorbidities. These methodological limitations highlight the need for a more tailored assessment of cancer incidence in KTRs compared to a well-matched general population.
This national study investigated the incidence of de novo malignancies among Korean KTRs by using a matched cohort designed to compare the cancer risk of KTRs with that of the general population. We aimed to evaluate the incidence of cancer following KT and assess the impact of pre-existing comorbidities on cancer occurrence. Identifying the elevated cancer risk and specific cancer types with increased incidence in KTRs is essential for informed decision-making before transplantation and for guiding evidence-based surveillance strategies post-KT.
Methods
Ethical statement
This study was approved by the Institutional Review Board of the Samsung Medical Center in compliance with the Declaration of Helsinki (No. 2023-01-006). The requirement for informed consent was waived because of the anonymized and de-identified data collection.
Data source and study population
We conducted a nationwide, population-based, retrospective cohort study using the Korean National Health Insurance Service (NHIS) database spanning January 1, 2004 to December 31, 2020. Adults aged ≥20 years who underwent KT during this period were identified (n = 25,361). The NHIS provides mandatory universal coverage for 97% of the South Korean population, with the remaining 3% covered by Medicaid beneficiaries. The Korean NHIS database includes nearly the entire population of South Korea and has been widely utilized for epidemiological studies [8–10]. This database comprises an eligibility dataset (including demographic variables such as age, sex, disability type and severity, socioeconomic variables, and income level) and a medical treatment dataset (containing claims data submitted by healthcare providers).
Inclusion and exclusion criteria
Participants with complete baseline information who received KT surgery (code R3280) or were diagnosed as kidney transplant status (code Z94.0) during the study period were included. The inclusion and exclusion processes are illustrated in Fig. 1. A total of 22,947 KTRs were included in the final analysis after excluding individuals with (1) missing baseline demographic or clinical data (n = 464), (2) a history of malignancy before KT (n = 1,243), and (3) death or cancer occurrence within 1-year post-KT to minimize detection bias (n = 707).
Control group selection and matching
Each KTR was matched to five individuals from the general population via incidence-density sampling based on age, sex, and calendar year of transplantation. Controls had no history of KT or cancer prior to the index date. We chose a 1:5 matching ratio to improve statistical efficiency and precision while maintaining analytic feasibility. Epidemiologic principles support that increasing the control-to-case ratio up to 4:1 or 5:1 substantially enhances power without incurring substantial inefficiency [11,12].
Covariates
Socioeconomic status was determined from household income and dichotomized at the lowest 20th percentile, including Medicaid beneficiaries, according to the NHIS premium categorization. Comorbidities were defined based on the prescription records at baseline as follows: diabetes mellitus (use of at least one oral antidiabetic agent or insulin), hypertension (use of at least one antihypertensive medication), and dyslipidemia (use of at least one lipid-lowering agent).
Outcomes and follow-up
The primary outcome was the incidence of newly diagnosed malignancies 1 year after KT. Cancer cases were identified using the International Classification of Diseases, 10th Revision, codes for malignancies (code C0–97). We evaluated the incidence and relative risk of specific cancers based on their prevalence in KTRs (e.g., kidney, bladder, skin, and hematologic malignancies) as well as those common in the general Korean population (e.g., stomach and thyroid cancers). Follow-up started 1 year post-KT and continued until the earliest occurrence of cancer diagnosis, death, or the study endpoint.
Statistical analysis
Baseline characteristics are summarized using means with standard deviations for continuous variables and frequencies with percentages for categorical variables. The incidence rate of cancer is expressed per 1,000 person-years. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer risk after adjusting for age, sex, income, diabetes mellitus, hypertension, and dyslipidemia. Stratified analyses were performed according to age groups (20–39, 40–54, and ≥55 years). All statistical analyses were conducted using SAS version 9.4 (SAS Institute), with the significance threshold set at p < 0.05.
Results
Baseline characteristics of the study population
The cohort comprised 137,682 participants (22,947 KTRs and 114,735 age and sex-matched members of the general population), with a mean follow-up duration of 6.6 ± 4.44 years. The mean age of KTRs at the time of KT was 47.4 ± 11.39 years, and men accounted for 59.7% of the cohort. Table 1 presents the baseline characteristics of the KTRs compared with those of the matched general population. The KTRs had a higher prevalence of diabetes mellitus, hypertension, and dyslipidemia and tended to have lower income levels than the matched general population. The residential areas were similar between the two groups.
Incidence rate and relative risk of cancer
During the study period, the overall incidence of cancer was significantly higher in KTRs than in the general population (10.32 vs. 5.98 per 1,000 person-years, p < 0.001). KTRs exhibited a consistently higher cumulative incidence of any cancer throughout the follow-up period (Fig. 2). Table 2 shows the incidence rates and HR according to malignancy type. The incidence rate for overall cancer was 10.32 in the KTRs and 5.98 in the matched general population. Models were adjusted for the following variables: none in Model 1; age and sex in Model 2; and age, sex, income level, and comorbidities (diabetes mellitus, hypertension, and dyslipidemia) in Model 3. A multivariable-adjusted analysis revealed an HR of 1.56 (95% CI, 1.45–1.67) for overall cancer. The incidence rates of stomach, thyroid, oropharynx, kidney, bladder, nervous system, skin, and hematologic malignancies including lymphoma and leukemia were significantly higher in KTRs than in the matched general population. Specifically, KTRs exhibited markedly elevated HR for kidney (HR, 6.64; 95% CI, 5.02–8.78), bladder (HR, 2.56; 95% CI, 1.79–3.66), skin (HR, 6.89; 95% CI, 5.11–9.28), stomach cancers (HR, 1.34; 95% CI, 1.10–1.62), and lymphoma (HR, 7.03; 95% CI, 1.75–28.18 for Hodgkin; HR, 5.69; 95% CI, 4.06–7.97 for non-Hodgkin). The wide CI for Hodgkin’s lymphoma was attributable to the small number of observed events. However, the incidence rates of colorectal cancer (HR, 0.77; 95% CI, 0.63–0.93) and hepatocellular carcinoma (HR, 0.67; 95% CI, 0.53–0.86) were lower in KTRs than in the general population. The risks of cancer in the pancreas, lung, esophagus, biliary tract, larynx, multiple myeloma, breast, cervix, ovary, endometrium, and prostate were comparable between KTRs and the matched general population.
Stratified incidence rate by age and sex according to cancer type
We conducted further analyses of the incidence rates and HR of cancer development stratified by sex and age (Table 3). In both men and women, KTRs exhibited a consistently higher incidence of cancer than the general population (male, 6.05 vs. 10.20 per 1,000 person-years; female, 5.87 vs. 10.49 per 1,000 person-years) (Fig. 3). Across all age groups, KTRs showed a consistently higher incidence of cancer, with a persistent gap throughout the 15-year follow-up period (20–39 years, 2.35 vs. 5.96 per 1,000 person-years; 40–54 years, 5.74 vs. 9.68 per 1,000 person-years; ≥55 years, 11.65 vs. 18.11 per 1,000 person-years) (Fig. 4). Although most subgroup analyses revealed findings consistent with those observed in the overall cohort, male KTRs demonstrated a reduced risk of colorectal, liver, and pancreatic cancers. Furthermore, the risks of breast cancer, gynecological cancer (excluding ovarian cancer), prostate cancer, and multiple myeloma were only elevated in the 20–39-year age group. KT exerted a greater impact on the occurrence of renal cancer and lymphoma in the 20–39-year age group than in the other age groups (p for interaction, <0.05).
Discussion
This nationwide cohort study investigated the incidence and relative risk of cancer among KTRs compared with those among an age- and sex-matched general population. KTRs showed a significantly higher overall incidence of malignancies, particularly kidney, bladder, skin, and stomach cancers and lymphomas, but a lower incidence of colorectal cancer and hepatocellular carcinoma than the general population. Notably, male KTRs showed a relatively lower incidence of colorectal, liver, and pancreatic cancers. These data provide valuable epidemiological insights into the risk of cancer post-KT and reinforce the need for tailored cancer screening and surveillance strategies for KTRs.
The increased risk of cancer in transplant recipients compared with the general population has been reported in previous studies conducted in the United Kingdom and the United States, where the overall cancer incidence rate was over twice that of the general population [6,7]. In the United States, non-Hodgkin lymphoma (NHL) is the most common cancer, followed by lung cancer, prostate cancer, and liver cancer. The standardized incidence rates are the highest for Kaposi sarcoma, lip cancer, non-melanoma skin cancer (NMSC), and liver cancer [7]. In the United Kingdom, NMSC and NHL are the most frequently observed, with higher standardized incidence rates for lip cancer, NMSC, Kaposi sarcoma, NHL, and anal cancer [6]. In contrast, thyroid and renal cancers were the most frequently reported cancers in our KTR cohort, whereas Hodgkin’s lymphoma showed the highest relative risk compared with that in the general population (although with a wide CI due to the small number of cases), followed by skin cancer, renal cancer, and NHL. Considering that thyroid cancer incidence in Korea increased 6.4-fold due to screening-detected small tumors [13], the high incidence in KTRs likely reflects detection bias from intensive surveillance. Although Kaposi sarcoma is a recognized posttransplant malignancy, events were exceedingly rare in our cohort rendering adjusted effect estimates not reliably estimable; therefore, we report descriptive counts and incidence rates only.
The increased risk of certain cancers among KTRs can be attributed to several factors. Long dialysis duration and acquired cystic kidney disease in native kidneys have been suggested as risk factors for renal cell carcinoma [14,15]. Additionally, ultraviolet light exposure and long-term immunosuppressive therapy after KT are known factors contributing to the development of skin cancer [16–18]. Specific immunosuppressive agents used for induction or antirejection therapy, such as anti-thymocyte globulin and interleukin-2 receptor inhibitors, and Epstein-Barr virus seronegativity, have also been associated with an elevated risk of posttransplant lymphoproliferative disease (PTLD) [16,19].
Previous studies have reported an increased risk of colorectal cancer among transplant recipients compared with the general population [4,6,7,20]. However, in our study, the reduced incidence of colorectal and liver cancers in KTRs, particularly among men, represented an intriguing finding. This discrepancy may be attributed to active medical surveillance and thorough pretransplant workups including mandatory endoscopy and abdominal imaging tests in South Korea, which facilitate the early detection and management of precancerous lesions. Pretransplant screening, including assessments for viral infections and malignancies, has been widely recommended [21–23]. The KDIGO (Kidney Disease: Improving Global Outcomes) guidelines emphasize the importance of comprehensive cancer screening for transplant candidates as per general population guidelines [24,25], and the screening should include several antiviral marker tests, chest computed tomography, esophagogastroduodenoscopy, colonoscopy, breast ultrasound, and abdominal ultrasound. Screening colonoscopy significantly reduces the risk of colorectal cancer in both the general population and KTRs [26,27]. Similarly, screening for hepatocellular carcinoma with abdominal ultrasound is well-documented to lower mortality in both low- and high-risk populations [28,29]. These findings underscore the critical role of systematic pretransplant screening programs for reducing cancer risks in KTRs. However, this paradoxical decrease might also be influenced by competing risks; higher non-cancer mortality (e.g., from cardiovascular disease or infection) in KTRs may preclude the development of these late-onset malignancies. Furthermore, strict selection criteria for transplantation often exclude candidates with severe comorbidities or poor lifestyle habits associated with these cancers, potentially introducing a ‘healthy candidate effect’ or selection bias.
Given the significantly elevated cancer risk in KTRs, there is a critical need for tailored cancer screening and prevention programs. Strategies such as adjusting immunosuppressive regimens to prevent PTLD, minimizing ultraviolet light exposure, and implementing targeted screenings for high-risk cancers could help reduce the risks of related cancers [19]. Furthermore, gastric cancer, one of the most common malignancies in South Korea, also showed a significantly higher risk in KTRs than in the general population, highlighting the importance of screening for it in posttransplant cancer surveillance in regions with high incidence. Notably, bladder cancer also exhibited a distinct pattern, being more frequent in younger KTRs. Prior exposure to cyclophosphamide for younger patients with rapidly progressive glomerulonephritis [30,31], BK virus reactivation [32,33], or age-related differences in cancer surveillance and competing mortality [34] might be associated with these results. Given the distinct risk profiles observed in our cohort, post-KT surveillance protocols should be tailored to prioritize gastric, renal, bladder, thyroid, skin, and lymphoid cancers, which demonstrated the highest risk elevations compared with the general population.
Our study has some limitations. First, identifying the causal relationships was challenging because of the retrospective study design. Prospective studies are warranted to validate these associations and explore the underlying mechanisms. Second, this nationwide cohort reflects South Korea’s unique healthcare system, where the national health insurance system provides universal health coverage including that for transplant candidates, and ensures access to a variety of screening tests. The relatively low medical costs in South Korea enable thorough pretransplant screening, which typically costs approximately USD 1,500–2,000 for an entire workup. This is notably lower than in the United States, where the average cost of a colonoscopy alone ranges from USD 2,400 to 2,750. Although these workup processes have been shown to reduce cancer risk, their applicability to other countries with different healthcare systems may be limited. Nevertheless, our findings indicate that active pretransplant screening may help lower cancer risk post-KT. Third, the follow-up period may appear relatively short for assessing malignancy risk after KT, as follow-up ended at the time of death or cancer diagnosis. However, the mean time to cancer occurrence in our study was 6.4 ± 4.37 years, which is comparable to the previous large cohort studies reporting time to malignancy, particularly for posttransplant lymphomas and other early-onset cancers [4,35]. Thus, the duration might be adequate for estimating overall cancer risk in this context, though longer-term follow-up is needed to fully evaluate late-onset malignancies and the long-term effects of immunosuppressive therapy. In addition, time-related trends may alter absolute risk attributed to KT per se with extended observation, underscoring the value of future analyses stratified by time since KT. Finally, we could not evaluate the impacts of detailed immunosuppressive regimens, donor type, and lifestyle factors such as diet, smoking, alcohol consumption, and physical activity, which may play a significant role in modulating cancer risk and incidence. Future research should incorporate prospective designs, diverse healthcare settings, detailed data on immunosuppressive regimens or donor type, and lifestyle factors to provide a more robust understanding of cancer risk in KTRs.
In conclusion, this study supports the clinical importance of individualized assessment and active surveillance of cancer in KTRs. By identifying specific malignancies with an increased risk after KT, our data may support future studies for establishing evidence-based clinical guidelines with a specified cancer screening program and optimizing posttransplant care of early detection and better outcomes. Further prospective studies including diverse healthcare systems are warranted to validate these findings, refine screening strategies, and clarify the impact of immunosuppressive modifications and underlying mechanisms.
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