This study provides a granular single-center real-world analysis of de novo urothelial carcinoma (UC) in kidney transplant recipients (KTRs), focusing on incidence, clinical presentation, treatment patterns, and both oncologic and graft-related outcomes. Despite being less common than renal cell carcinoma (RCC) in transplant cohorts, UC remains a clinically relevant malignancy, with diagnostic and therapeutic challenges due to the complex interplay of an aggressive entity, immunosuppression, chronic kidney disease (CKD), and the presence of a transplant.

In our cohort of 4,012 KTRs, 19 developed UC during follow-up, corresponding to a standardized incidence ratio (SIR) of 2.21, which indicates a moderately increased risk compared with the general population and aligns with registry-based analysis and meta-analysis reporting SIRs between 1.9 and 3.6 for UC after solid organ transplantation [1, 2, 20, 21]. For context, the SIR was lower than in our previous renal cell carcinoma (RCC) transplant cohort, but the present work focused on UC-specific patterns, particularly upper-tract and graft-involving disease [3].

A striking finding is the high proportion of upper-tract urothelial carcinoma (UTUC) in this cohort (31.6%), including three tumors involving the renal allograft, whereas UTUC represents only a small fraction of UC in the general population [4]. In contrast to several East Asian series reporting a female predominance and an even higher relative burden of UTUC and graft-involving tumors, our cohort was predominantly male, suggesting that regional and environmental exposures, such as aristolochic acid, may modulate disease patterns [4, 7]. Mechanistically, this distribution likely reflects a combination of transplant-related and regional risk factors, including aristolochic acid exposure, BK polyomavirus reactivation, ischemic injury, and long-term immunosuppression [4, 7, 10, 11].

Tumors arising in the transplanted kidney or ureter present clinical challenges due to the potential need for transplant nephrectomy, which directly jeopardizes graft function. In our cohort, nearly half of the patients experienced graft failure, and four cases were directly attributed to UC progression. These numbers reinforce findings from multi-center registries reporting graft-involving UC as a rare but impactful event [5, 14].

The median latency between transplantation and UC diagnosis was 47 months, which is somewhat shorter than previous reports of median latencies of 7–10 years [1]. However, the wide range (1–149 months) observed in our cohort highlights the need for lifelong surveillance. Several tumors in our series were detected incidentally, emphasizing that reliance on symptom-driven evaluation (e.g., macrohematuria) may result in delayed diagnosis.

Histologically, conventional UC dominated, and most patients had non–muscle-invasive disease (pTa or pT1). Still, 15.8% had muscle-invasive tumors (≥pT2), and 10.5% had distant metastases at diagnosis. Four patients (23.5%) developed metachronous metastases. While direct comparisons to immunocompetent populations are limited, our findings support prior reports suggesting a more aggressive disease course in immunosuppressed patients, potentially due to impaired immune surveillance, limited treatment options, and diagnostic delays [3, 6].

Therapeutic decision-making in this population remains complex. Several patients underwent radical surgery, including nephroureterectomy and cystectomy, and transplant nephrectomy was required in three patients—two for oncologic control and one due to graft failure. The need to balance oncologic efficacy against the risk of losing graft function is a core dilemma in this setting, particularly when the graft is directly involved.

Only two patients received intra-vesical therapy (one with BCG, one with mitomycin). The low use of BCG reflects clinical concerns over systemic infection and reduced efficacy under immunosuppression. While some case series suggest BCG may be safe in selected KTRs [15, 16], this remains controversial and requires individualized risk–benefit assessment.

Systemic therapy options are also limited. Platinum-based chemotherapy, the standard of care for advanced UC, is associated with nephrotoxicity and myelosuppression. Immune checkpoint inhibitors (ICIs), now integral to the treatment of metastatic UC, are rarely used in KTRs due to the high risk of allograft rejection—reported in up to 50% of patients [12, 17]. In our series, only three patients received systemic chemotherapy, and none received immunotherapy. This therapeutic gap underscores the urgent need for alternative treatment strategies for transplant recipients with advanced UC.

Despite these limitations, overall survival (OS) outcomes were relatively favorable: the 3-year OS was 70%, and the 5-year OS was 51%. However, these are inferior to our previous RCC transplant cohort (5-year OS: 72%) [18], again highlighting the potentially more aggressive behavior of UC in the transplant setting. UC was the cause of death in three of ten deceased patients (30%), with the remainder attributed to other malignancies, infections, or unknown causes.

From a diagnostic standpoint, our data—together with prior reports describing diagnoses well beyond a decade post-transplant [12, 13]—underscore the importance of tailored, risk-adapted surveillance protocols in KTRs. At our center, KTRs undergo structured post-transplant follow-up primarily focused on graft function, with regular clinical visits, laboratory monitoring, and ultrasound, whereas urologic evaluation is usually triggered by symptoms such as hematuria, recurrent urinary tract infections, unexplained graft dysfunction, or suspicious imaging findings. Annual ultrasound alone is unlikely to reliably detect early UC, particularly in the upper tract or transplanted kidney, and the wide latency range combined with a substantial burden of upper-tract and graft-involving tumors supports a risk-adapted lifelong surveillance approach Fig. 3. A low threshold for evaluating macroscopic or persistent microscopic hematuria with cystoscopy and upper-tract imaging appears warranted, and in patients with elevated risk—such as recurrent or persistent hematuria, recurrent infections, BK virus replication, smoking history, prior urothelial lesions, or suspected aristolochic acid exposure—intensified surveillance with periodic urine cytology and cross-sectional upper-tract imaging may be considered in addition to routine ultrasound-based follow-up.

Proposed risk-adapted lifelong surveillance algorithm for urothelial carcinoma in kidney transplant recipients. The algorithm differentiates recipients without additional risk factors from those with ≥ 1 risk factor (e.g., smoking history, BK virus replication/viremia, suspected aristolochic acid exposure, prior UTUC, persistent hematuria) and outlines suggested triggers and diagnostic modalities (cystoscopy, cytology, and risk-adapted upper-tract imaging with escalation to CTU/MRU when clinically indicated)

This study has several limitations. First, the cohort is small because UC in KTRs is rare, which precluded multivariable analysis and age- or sex-stratified SIR estimation and necessitated an observed-to-expected approach using national reference rates. Second, the retrospective design relies on routine documentation; events occurring entirely outside our health system may have been missed, detailed information on aristolochic acid exposure, viral reactivation, and the exact anatomic sublocalization of graft-involving tumors was incomplete, and recurrence as well as cause-of-death attribution were not captured in a standardized manner across the full study period. Third, graft survival and metastasis-free survival were estimated using Kaplan–Meier methods without formal competing-risk modeling, which may overestimate event-free survival in a population with substantial competing mortality and should be refined in larger multi-center cohorts. Nevertheless, the structured transplant follow-up, high completeness of core data, and parallel reporting of oncologic and graft outcomes represent important strengths.