Research on the causes and risk factors of cancer is vital for formulating health policies encompassing diagnosis, treatment, and prevention. Our study, utilizing large-scale data from approximately 360,000 individuals, revealed an increased risk of GU cancer in KTRs. Although retrospective and observational in design, large-scale studies focusing on Korean populations are scarce. To minimize bias, we employed 1:3 propensity score matching between patients who had received KT and those who had not, allowing for a comparative analysis of the incidence of GU cancer. We used sex and age as covariates for matching because the risk of developing GU cancers, including prostate, bladder, and kidney cancers, is generally known to increase with age and vary by sex. Additionally, considering that our data spanned over a decade, we adjusted for the year of registration to reduce bias owing to temporal variations in cancer incidence rates.
However, this study has some limitations. We were unable to perform subgroup analyses based on sex and age primarily because of time constraints in obtaining approval for data usage from the government. This is especially pertinent for interpreting results for cancers such as prostate cancer, which only occurs in men. In terms of sex differences, previous studies have reported an increased risk of bladder and kidney cancer in male KTRs than in females [9, 10]. Second, although alcohol consumption and smoking are known risk factors for various cancers, and factors related to metabolic syndrome (e.g., diabetes, hypertension, and obesity), along with lifestyle elements such as exercise and diet, are reported to be associated with cancer incidence, many of these factors were missing from our dataset and thus could not be included in our analysis. Therefore, when examining the association between KT and the risk of GU cancer, we could only adjust for a limited set of risk factors, including age, sex, diabetes, hypertension, and hypercholesterolemia. Consequently, although our study was large-scale, the accuracy of its findings should be interpreted with caution.
KTRs require long-term use of immunosuppressive agents such as prednisone, mycophenolate mofetil, cyclosporine, and tacrolimus, all of which disrupt IL-2 production, thereby inhibiting cell-mediated immune responses [11–13]. These agents impede the recruitment of lymphocytes to inflammatory sites and suppress the production of cytokines by innate immune cells, such as dendritic cells, macrophages, and neutrophils, thereby affecting T cell priming and response [13]. The role of T cells in anti-tumor immunity, known as the “cancer immunity cycle,” is well-documented [14, 15]. These facts theoretically support our findings of an increased risk of GU cancer in KTRs exposed to long-term immunosuppression, while other studies have reported an increased risk of bladder and kidney cancers in similar contexts [5–7]. Notably, an elevated risk of kidney cancer has been observed in KTRs who have received long-term treatment with immunosuppressive agents, such as cyclosporine or mycophenolate mofetil [7]. Furthermore, liver transplant recipients, another group that maintains an iatrogenic immunosuppressive status, have been shown to have a higher risk of kidney cancer than healthy individuals [16]. Therefore, the increased risk of kidney and bladder cancers in KTRs has been repeatedly confirmed not only in our Korean cohort but also in multiple multinational cohorts.
Patients with ESKD are often unable to adequately eliminate inflammatory cytokines, and persistent uremia can impair lymphocyte proliferation and maturation [17, 18]. These factors induce abnormal innate and adaptive immune responses, a phenomenon observed in ESKD that does not improve with treatments, such as dialysis or KT [17]. Therefore, dysregulated immune responses against tumors may be present in KTRs, contributing to their increased risk of GU cancer [17–19].
Recently, systemic anticancer treatments for kidney and bladder cancers have increasingly focused on immune checkpoint inhibitors, which reactivate cytotoxic T cells and are becoming a mainstay of therapy [20, 21]. However, KTRs, who must maintain a state of immunosuppression to prevent graft rejection, and who have biologically dysregulated immunity because of ESKD, face challenges in benefiting from these advanced therapeutic options. Thus, our findings highlight the need for screening tests to enable the earlier detection of GU cancer in KTRs, potentially increasing the opportunity for surgical intervention. However, further research is required to analyze the mortality reduction benefits and cost-effectiveness of GU cancer screening.
The observed increased risk of GU cancer among KTRs is theoretically persuasive. However, similar to our findings, other research has also reported no significant association between KT and an increased incidence of prostate cancer [22, 23]. In contrast, a large-scale study reported a significantly higher risk of prostate cancer in KTRs than in an age-matched healthy population [24]. Therefore, this area warrants further investigation and comparative studies across different cohorts.
In conclusion, our large-scale national cohort study in the Korean population suggests that, compared to the general population, KTRs may have an increased risk of GU cancers, including bladder and kidney cancers. Our findings will assist transplant physicians in providing better pre- and post-KT counseling, and provide pivotal evidence for the development of cancer surveillance programs for KTRs in South Korea.