Kidney transplantation (KTX) is a standard treatment for patients with end stage renal disease (ESRD). For patients under dialysis, KTX prolonged overall survival (OS) and improved life quality (1, 2). Malignancy, infection and cardiovascular disease are the leading causes of mortality and morbidity in KTX recipients (3–7).

KTX recipients have a cancer incidence rate approximately twofold to fourfold higher than the age- and gender- matched general population. The main mechanisms of an elevated malignancy incidence rate are likely the long-term immunosuppress agents use, carcinogenic virus infection, and donor transmission (8–17). Immunosuppressants use with an increasing risk of carcinogenic virus infection may be the cause of post-transplantation cancer occurrence, such as liver cancer caused by hepatitis B virus. Risk increased for common cancers in the general population, for example, skin, lung and kidney cancer, which may be attributable to multi-factors, including immunosuppression, carcinogenic medication, or end stage renal disease (18–20). Certain cancer types (breast and prostate cancer) have decreased incidence after kidney transplantation for unknown reasons (12, 13).

Improvement in post-kidney transplantation care results in a longer graft survival and a reduction in recipient mortality caused by infection or cardiovascular events (3–7). Meanwhile, a longer survival may contribute to an increased incidence of post-transplantation malignancy. Despite recent advancement in cancer management, it is challenging in managing transplantation recipients with cancer when preserving renal function at the same time (21–28).

In view of the increased risk of post-kidney transplantation malignancy and improved cancer treatment, we conducted here a cohort study to evaluate the variation in cancer incidence and outcomes for kidney transplantation recipients in the past two decades.

In this study, we found that patients with KTX were associated with a higher risk of malignancy when compared with the general population. Recipients with post-KTX malignancy had worse overall survival compared with the general population with malignancy. There was no significant change in cancer incidence for KTX recipients over the past 20 years, but graft failure and mortality rates decreased in the recent decade.

Previous studies reported higher malignancy risks of 2 to 4-fold in kidney transplantation recipients compared with the general population (8–17). In this study, we found that such patients had an increased risk of developing malignancy following kidney transplantation (SIR:1.635) compared with the general population. The slightly lower SIR is likely related to the fact that we excluded patients with history of malignancy before transplantation. In general, most sites of cancer presented higher SIR compared with the general population. On the other hand, breast and prostate cancer did not show an elevated risk, the real reason was unclear, and this finding was consistent with the study conducted by Engels et al. (12).

A higher risk of malignancy for KTX recipients may be resulted from several factors (16). Immunosuppression may be the reason for virus induced cancers. For example, hepatitis B virus and hepatitis c virus for liver cancer, and human T cell lymphotropic virus for non-Hodgkin lymphoma. On the other hand, for non-virus mediated cancers, including common cancers in general population (lung, colon, breast, and prostate cancer) and ESRD patients (kidney and bladder cancer), closer cancer screening tests may have contributed to a higher incidence rate for those patients (18–20).

The mortality rates between KTX patients with cancer and the general population with cancer were debatable. Kiberd et al. reported that there was no difference in cancer mortality between these two populations (29). However, some studies report a higher mortality rate for patients with PTM compared with the general population (30–32). In this study, we found that the overall survival of KTX recipients was worse for those with PTM compared with the general population for most cancer types and overall malignancy (HR 1.115 95% CI 1.071-1.763 P < 0.0001). The results indicated a challenging condition in treating these KTX recipients with malignancy under immunosuppressants, which may limit the use of chemotherapy or immunotherapy.

Previous reports on the median time from kidney transplantation (KTX) to cancer diagnosis have been limited and variable, ranging from 2.6 to 4 years (32, 33). In our study, the interval from KTX to cancer diagnosis was comparatively shorter (2.54 years). This difference may be attributable to more intensive cancer screening following KTX as well as the increasing use of marginal donors and recipient. Importantly, these results highlight the need for closer surveillance for common post-transplant malignancies.

The use of mammalian target of rapamycin (mTOR) inhibitors has been associated with a reduced incidence of malignancy in several studies (28, 34, 35). However, conflicting evidence has been reported regarding the cancer risk associated with sirolimus use in recipients (36, 37). A meta-analysis by Knoll et al. indicated that the anti-cancer benefits of sirolimus were primarily observed in patients who were converted from other immunosuppressive regimens, rather than in those who received de novo sirolimus (34). Furthermore, de novo use of sirolimus was associated with an increased risk of post-transplant lymphoproliferative disorder (38). In our study, multivariate analysis revealed that the use of mTOR inhibitors was associated with an increased risk of PTM (HR 1.306–95 CI 1.218-1.401). Previous studies have shown that calcineurin inhibitors (CNIs), such as cyclosporin and tacrolimus, are associated with a heightened risk of PTM, potentially due to their immunosuppressive or carcinogenic properties (32, 39). Consistent with these findings, multivariate analysis identified tacrolimus (HR 1.135–95 CI 1.098-1.173) and cyclosporin (HR 1.284–95 CI 1.214-1.358) as risk factors for PTM when used as maintenance immunosuppressive therapies. Notably, we did not observe a significant association between elevated serum tacrolimus levels and PTM. This may be attributed to the dynamic nature of tacrolimus serum levels and the lack of standardized timing for level measurement in the TriNetX database. These findings underscore that immunosuppression remains a key factor for PTM, regardless of the specific regimen used. Therefore, enhanced cancer surveillance is warranted in kidney transplant recipients (24, 40, 41).

Blosser CD, et al. and Piselli P, et al. reported that there was no significant change in incidence of PTM over time (42, 43). Our results align with previous evidence, indicating that the overall incidence of PTM has remained relatively stable over the last twenty years. In the unadjusted analysis, increased incidences of kidney, prostate, and overall cancer were observed. These findings may be attributable to the older age of recipients and the increased intensity of cancer screening in recent years. However, after adjusting for these factors, the overall cancer incidence did not show a significant increase over the past two decades. Blosser et al. previously reported no significant improvement in graft or patient survival among kidney transplant recipients with non-Hodgkin lymphoma (non-NHL) malignancies (42). In contrast, our study demonstrated a decline in both graft failure and patient mortality among recipients diagnosed with PTM over the past two decades. Although the exact mechanisms underlying these observations remain unclear, the trends may be partially attributable to improvements in post-transplantation care, including advancements in oncologic treatments and the management of infectious and cardiovascular complications, which could positively influence graft and patient survival.

This study has several limitations inherent to its retrospective design, including the possibility of residual confounding despite adjustment for known covariates. The use of the TriNetX database, while providing a large sample size, is limited by the absence of detailed cancer-specific outcome metrics such as tumor staging, histopathology, treatment modalities, and cause-specific mortality, which restricts the depth of interpretation. Additionally, the reliance on administrative coding may introduce misclassification bias in diagnoses and outcomes. Selection bias is also a concern, as the dataset represents patients from specific healthcare organizations and may not fully generalize to the broader transplant population. Furthermore, patients in the more recent transplant cohort may have shorter follow-up durations, potentially leading to an underestimation of cancer incidence in this group. Lastly, we defined PTM as any cancer diagnosis occurring ≥1 month following kidney transplantation. It is acknowledged that this definition may inadvertently capture malignancies that were present but undiagnosed at the time of transplantation. Despite these limitations, our research was a population-based study with a large sample size, which may avoid some bias arising from its retrospective nature. Furthermore, data regarding the trends of PTM over the past decades was limited, and our research provided information on this topic.

In conclusion, KTX recipients exhibited a significantly higher risk of PTM compared with the general population. Moreover, the presence of PTM was associated with increased overall mortality. Although the incidence of PTM has remained stable over the past two decades, both graft failure and mortality risks among patients with PTM have shown a significant decline during the same period.