Stesura Seveso Archivio Italiano di Urologia e Andrologia 2023; 95, 1 ORIGINAL PAPER death, contributing to their excess mortality in compari- son to the general population (2). Therefore, until recent- ly, any form of active neoplasia was regarded as a con- traindication to renal transplantation, and a waiting peri- od between cancer treatment and transplantation was mandatory. The decision on the waiting period for transplantation in patients with a history of treated cancer is mainly based on the Cincinnati Transplant Tumor Registry (3), with times varying from two to at least five years, depending on the type of tumor. However, this study published more than twenty years ago has several drawbacks that may not reflect the actual epidemiology of current diag- nosed cancers: treatment and staging were not defined, and many diagnostic, therapeutic and prognostic tools have improved over these last years. Therefore, nowa- days, there is not enough evidence to support a fixed waiting period before transplantation. Besides, there is growing recent evidence suggesting that the increased risk of cancer by immunosuppression is restricted to particular subtypes, while others may not be affected. Cancers at highest risk are viral-induced cancers such as lymphomas and Kaposi sarcoma, and those caused by impaired immune surveillance or via direct DNA damage by anti-rejection drugs such as skin and lip cancers (4). Although renal cell carcinoma (RCC) of native kidneys is one of the most common tumors in renal trans- plant recipients, accounting for 8% of malignancies in this population (5), it has been shown that its incidence is lower during transplantation than during graft non- functioning periods without immunosuppression (6). A typical feature of ESRD is a higher incidence of RCC, where it can be up to ten times higher than the general population, being found in 4% of dialyzed or renal trans- plant patients (7). The main risk factor for RCC is acquired cystic kidney disease (ACKD), which increases with duration of dialysis (8), and seems to regress after successful transplantation. Thus, a longer waiting period for transplantation may paradoxically increase the risk of this kidney dysfunction-related cancer. Since the outcomes of RCC after kidney transplantation and its prognosis under immunosuppressive regimens remain poorly understood with conflicting evidence, we aimed to evaluate clinical and pathological characteristics of RCC of native kidneys in ESRD patients, and to com- pare the risk of recurrence and survival according to their dialysis or transplantation status at the time of diagnosis. Introduction: Kidney transplantation requires immunosuppression, traditionally regarded as a risk factor for progression in all malignancies. Based on the Cincinnati Registry, a waiting period before transplantation is therefore mandatory. However, recent evidence suggests this increased risk is restricted to particular tumors, whereas others like renal cell carcinoma (RCC) are not negatively affected. We aimed to compare oncological outcomes of RCC in native kid- neys of end-stage renal disease (ESRD) patients, according to their transplantation or dialysis status. Material and methods: Retrospective analysis of all ESRD patients diagnosed with RCC between 2010 and 2020 in our center. Recurrence-free survival (RFS) and overall survival (OS) were estimated with Kaplan-Meier curves. Multivariable Cox regression model was used to evaluate their association with kidney transplantation. Results: Clinical and pathological characteristics were similar between groups. Kidney transplant recipients had similar risk of recurrence (hazard ratio [HR] 0.40, 95% confidence interval [CI) 0.04-4.46, p = 0.458) and overall survival (HR 0.34, 95%CI 0.07-1.77, p = 0.202) as dialyzed patients. On multivariable Cox regression model, presence or absence of transplantation was not significantly associated with RFS (p = 0.479) or OS (p = 0.236). Time on dialysis was the only independent predictor of worse survival (HR 1.86, 95%CI 1.18-2.93, p = 0.008). Conclusions: Most RCC in native kidneys of ESRD patients are low-grade, low-stage and exhibit favourable pathological and outcome features. Immunosuppression does not seem to have an impact on oncological outcomes, but an increased time on dialy- sis seems to be associated with worse overall survival. Therefore, waiting time for transplantation for these tumors could be reduced. KEY WORDS: Kidney transplantation; Immunosuppression; Dialysis; Renal cell carcinoma; Recurrence; Overall survival; Waiting period. Submitted 6 February 2023; Accepted 17 February 2023 INTRODUCTION Renal transplantation is the most successful treatment for end-stage renal disease (ESRD) owing to its superior sur- vival and quality of life compared to other replacement therapies (1). However, it requires immunosuppression, traditionally being regarded as a risk factor for increased tumor incidence and progression. The increased inci- dence of cancer in this population is a significant cause of Renal cell carcinoma in native kidneys before transplantation - When will we stop waiting? Jorge Correia, Bernardo Teixeira, Gonçalo Mendes, Avelino Fraga, Miguel Silva-Ramos Department of Urology, Centro Hospitalar Universitário do Porto, Portugal. DOI: 10.4081/aiua.2023.11240 Summary Archivio Italiano di Urologia e Andrologia 2023; 95, 1 J. Correia, B. Teixeira, G. Mendes, A. Fraga, M. Silva-Ramos MATERIALS AND METHODS Study design and patient selection In this observational retrospective, single-center, cohort study, we evaluated data on all consecutive patients with ESRD diagnosed with RCC of native kidneys and submit- ted to radical nephrectomy between 2010 and 2020. Overall, 40 RCC cases were identified in this population based on post-operative histopathological staging. They were subsequently stratified according to their kidney transplantation or dialysis status at the time of diagnosis, and clinical, pathological and oncological outcomes were compared between groups. We excluded from analysis patients diagnosed with RCC while on dialysis who later received a renal transplant, and patients with regional or distant metastatic disease. Renal transplant patients diag- nosed with RCC, with later graft failure leading to resum- ing of dialysis were included in the kidney transplant cohort. Perioperative and socio-demographic data, clini- cal and histopathological characteristics and survival out- comes were extracted from medical records. Pre-operative staging and surgical technique All patents were evaluated preoperatively with computed tomography (CT) of the abdomen, pelvis and chest to con- firm localized disease, and with biochemical blood work with creatinine. All patients were treated with radical nephrectomy, per- formed by either an open approach through flank inci- sion or laparoscopic approach by standard transperi- toneal four-trocar technique, based on patient and sur- geon preference. Lymph node dissection was not per- formed in any patient, since there was no nodal involve- ment suspected based on preoperative imaging or intra- operatively enlarged nodes. All kidney transplant patients were on standard immuno- suppressive regimen, and no modification to this scheme due to oncological concerns was made at the time of RCC diagnosis or during follow-up. Pathological evaluation All surgical specimens were processed according to stan- dard pathological procedures. All lesions were confirmed to be malignant renal cell carcinomas. Tumors were staged according to the 7th edition of the American Joint Committee on Cancer TNM classification (9) and the his- tological subtype was assigned according to the 2016 World Health Organization (WHO) classification of kidney tumors (10). Tumors were graded according to the International Society of Urological Pathology grading classi- fication (11). Tumor multifocality was defined as the presence of two or more synchronous lesions in the same kidney, pathologically confirmed to be RCC. Tumor bilaterality was defined as the presence of synchronous lesions in both kidneys at the time of diagnosis. Follow-up Patients were followed every 6 months during the first year after surgery, yearly until 3 years, and once every 2 years thereafter. Follow-up consisted of medical history and appropriate physical examination, routine blood work and imaging re-evaluation. Oncological outcomes comprised recurrence-free survival (RFS) and overall survival (OS). Both survival outcomes were evaluated from the date of surgery to time of event or, when lost to follow-up, the last documented outpa- tient visit with his physician. Recurrences were treated with surgical excision, and patients continued on regular follow-up. Statistical analysis Categorical variables are presented as frequencies and percentages, and continuous variables as means and stan- dard deviations, or medians and interquartile ranges (IQR) for variables with skewed distributions. Normal distribu- tion was checked using Shapiro-Wilk test or skewness and kurtosis. Univariate logistic regression was used to investigate the association between baseline patient and pathological characteristics and the transplantation or dialysis status. Continuous variables were compared with the use of paired Student’s t-test or Mann-Whitney test for variables with normal and skewed distribution, respectively. Categorical variables were compared with the use of Table 1. PPLA score system for renal papillae (16). Kidney transplant Dialysis P value (n = 22) (n = 18) Demographic characteristics Age (years) 57.7 ± 11.0 57.7 ± 11.0 0.999 Sex, n (%) Male 19 (86%) 18 (100%) 0.238 Female 3 (14%) 0 (0%) ASA score, n (%) ≤ 3 21 (95%) 8 (44%) < 0.001 > 3 1 (5%) 10 (56%) BMI (Kg/m2) 25.0 ± 3.38 25.9 ± 3.04 0.387 Time on dialysis before diagnosis (months) (IQR) 38.5 (13-60) 28.0 (11-42) 0.430 Time on immunosuppression (months) (IQR) 136.5 (66-182) - - GFR (ml/min/1.73 m2), n (%) < 15 1 (5%) 18 (100%) < 0.001 15-30 4 (18%) - > 30 17 (77%) - Clinical and pathological characteristics Size (mm) 29.27 ± 16.78 38.11 ± 21.14 0.148 T stage, n (%) pT1a 18 (82%) 11 (61%) 0.184 pT1b 3 (14%) 5 (28%) pT2a 1 (4%) 0 (0%) pT2b 0 (0%) 0 (0%) pT3a 0 (0%) 2 (11%) Histological subtype, n (%) Clear cell 12 (55%) 8 (44%) 0.714 Papillary (type 1 and 2) 6 (27%) 8 (44%) Clear cell papillary 2 (9%) 1 (6%) Other 2 (9%) 1 (6%) ISUP grade, n (%) Grade 1-2 21 (95%) 11 (61%) 0.014 Grade 3-4 1 (5%) 7 (39%) Tumor multifocality, n (%) 3 (14%) 4 (22%) 0.680 Tumor bilaterality, n (%) 1 (5%) 1 (6%) 0.884 ASA = American Society of Anesthesiologists; BMI = Body mass index; GFR = Glomerular filtration rate; IQR = Interquartile range; ISUP = International Society of Urological Pathology. Archivio Italiano di Urologia e Andrologia 2023; 95, 1 Renal cell carcinoma and transplantation teristics were homogeneous between populations. Most of the patients had pT1a disease (82% transplant vs 61% dialysis, p = 0.184), with median tumor size 3-4 cm. The most frequent histological subtype was clear cell (cc) RCC, closely followed by papillary (pRCC) which was slightly more frequent in the dialysis group, albeit with- out statistically significant difference (p = 0.714). 3 (7.5%) patients presented with clear cell papillary RCC (ccpRCC). Dialyzed patients were more likely to have higher grade disease (5% kidney transplant vs 39% dial- ysis, p = 0.014). Overall, 7 (18%) and 2 (5%) patients presented with tumor multifocality and bilaterality respectively, similarly distributed between groups. Over a median follow-up of 41 months (IQR 22-71), 3 recurrences occurred: 1 in kidney transplants (from ccRCC) and 2 in dialyzed patients (1 ccRCC, 1 pRCC). All the 3 recurrences occurred in the contralateral kidney with the same histological subtype, and neither any of these recurrent patients nor from the remaining overall cohort later progressed to regional node or distant metastatic disease. Figure 1 shows the probability of freedom from recur- rence following nephrectomy according to kidney trans- plant or dialysis status. Median time to recurrence was not reached in any group (NR, 95% confidence interval (CI) not evaluable (NE) - NE), with 5-year RFS of 96% (95%CI 91-99) and 89% (95%CI 79-98) for kidney transplant and dialyzed patients, respectively (log-rank p = 0.443). Kidney transplant patients did not show an increased risk of recurrence [hazard ratio (HR) 0.40, 95%CI 0.04-4.46, p = 0.458]. On multivariable Cox Figure 1. Kaplan-Meier estimates of recurrence-free survival (A) and overall survival (B) following radical nephrectomy, comparing kidney transplant (Kidney Tx) and dialysis patients. Fisher’s exact test or the chi-square test, as appropriate. Kaplan-Meier survival curves were calculated for each group of ESRD patients and log-rank (Mantel-Cox) test calculated for difference or equivalence between treat- ment groups, censoring patients without the event at their date of last follow-up. A multivariate Cox propor- tional hazards regression model was fit with time to recurrence and time to death of any cause as the depend- ent variables, and clinical and pathological characteristics as the independent variables, to identify independent prognostic factors of RFS and OS. All reported p values are two-sided, with a p value less than 0.05 indicating statistical significance. Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS®), version 24.0 (IBM Corp., Armonk, NY, USA). RESULTS Demographic and pathological characteristics of the cohort stratified by kidney transplant or dialysis status at the time of diagnosis are shown in Table 1. Kidney trans- plant recipients and dialysis accounted for 22 (55%) and 18 (45%) patients, respectively. Mean age at the time of diagnosis was 58 years old, and the majority of patients in both groups were male (93% overall). Demographic characteristics were similar between groups, except for a lower ASA score being more common in the kidney transplant cohort (ASA score ≤ 3, 95% kidney transplant vs 44% dialysis, p < 0.001). Median time on dialysis until diagnosis was similar (p = 0.430). Pathological charac- Archivio Italiano di Urologia e Andrologia 2023; 95, 1 J. Correia, B. Teixeira, G. Mendes, A. Fraga, M. Silva-Ramos regression analysis (Table 2), adjusting for clinical and pathological confounders, presence or absence of kidney transplant (and consequently immunosuppression) was not significantly associated with RFS (HR 0.42, 95%CI 0.04-4.65, p = 0.479). Likewise, the time on immuno- suppression was not an independent predictor of RFS (HR 0.98, 95%CI 0.95-1.02, p = 0.322). There were 7 deaths during follow-up, 2 in kidney trans- plant and 5 in dialysis patients. No cancer-related deaths were seen. Most deaths were related to cardiovascular dis- ease (71% overall; 100% kidney transplant and 60% dial- ysis). Median time to death was not reached in any group (HR 0.34, 95%CI 0.07-1.77, p = 0.202). 5-year OS was 91% (95%CI 78-99) for kidney transplant recipients and 72% (95%CI 59-85%) for dialyzed patients (log-rank p = 0.181). On multivariable analysis, neither the presence or absence of transplantation (HR 0.04, 95%CI 0.01-7.78, p = 0.236) nor the time on immunosuppression (HR 1.00, 95%CI 0.98-1.02, p = 0.862) were significantly associated with OS. The only independent predictor of worse survival was time on dialysis (HR 1.86, 95%CI 1.18-2.93, p = 0.008). DISCUSSION Considering that malignancy is a major cause of death after transplantation, a systematic screening for the pres- ence of any active/latent cancer or a past history of cancer is mandatory when evaluating candidates for renal trans- plantation (12). However, previous history of malignancy and the role of immunosuppression as a causative risk factor for recurrence is still controversial, particular in certain subtypes of malignancy such as RCC, making it difficult to decide if the patient is suitable for transplan- tation and, if so, how long should the waiting period be. Few studies have focused on the oncological outcomes of native kidneys RCC in ESRD patients, all retrospective and most of them noncomparative, providing conflicting results. Farrugia et al. (2) have shown that previous history of neo- plasia was an independent risk factor for post-transplant death from malignancy. In a large Swedish cohort of more than 10000 solid organ transplant recipients, Brattström et al. (13) have found a 30% increased mortality risk for patients with a previous history of neoplasia. Nevertheless, this risk was mainly driven by recipients of non- kidney transplants: mortality was increased by 20% in kidney recipi- ents and by 80% among other organs recipients. Besides, after stratification by waiting time between cancer treat- ment and transplantation, there was no association of increased mortality in kidney recipients, irrespective of waiting period. A two-fold increased risk of cancer-specific death was seen in transplant patients with a history of previous cancer other than kidney compared to RCC, regardless of wait- ing time. On the contrary, Viecelli et al. (14), using data from the Australian and New Zealand Dialysis and Transplant Registry, reported no significant association of previous cancer history with cancer-specific survival (CSS) or OS in kidney transplant recipients. Similarly, a recent nation- wide Norwegian study found that kidney recipients with a history of neoplasia had a similar OS and graft survival as recipients without such cancer, and although cancer mor- tality was increased, particularly during the first 5 years, a short waiting period was not associated with all-cause or recurrent cancer mortality (15). In line with the most recent evidence, in our cohort, kid- ney transplant patients did not have an inferior RFS or OS compared to dialyzed patients. Moreover, on multivari- able Cox regression model, the presence or absence of transplant (and consequently immunosuppression) was not significantly associated with the risk of recurrence or increased mortality. In fact, the only independent predic- tor of an inferior survival was time on dialysis (HR 1.86, p = 0.008), which means that the common policy of a 2- year waiting period before transplantation would trans- late into a 3-4-fold increased risk of death. Cardiovascular disease remains a major cause of death in dialyzed patients (16) and since most ESRD patients are elderly, it is possible that a longer waiting period will eventually lead to death, not due to cancer recurrence, but due to the burden of dialysis (17). Reducing unnec- essary lengthy waiting times could improve the care of these patients, optimizing timely transplantation. In accordance with our results, several studies have shown the safety of transplantation and immunosuppres- sion in patients with a history of native kidney RCC. In a multicentric study from 24 centres conducted by the French Urological Association, Gigante et al. (18) com- pared oncological outcomes of RCC in 213 transplanted and 90 dialyzed patients and reported higher 5-year RFS and CSS in the transplanted population. On multivariable analysis, presence of kidney transplant was not associat- ed with CSS, with only T stage remaining an independent predictor of inferior survival. Similarly, in a single-centre study comparing outcomes of native kidneys RCC in renal transplant recipients with a population with RCC without transplant, Klatte et al. (19) showed that the pres- ence of transplant did not affect CSS and OS, and that most RCC were low-stage, low-grade with a favourable Table 2. Multivariable Cox regression model predicting RFS and OS after radical nephrectomy. RFS OS Hazard ratio 95% CI p value Hazard ratio 95% CI p value Kidney transplant, yes vs no 0.42 0.04-4.65 0.479 0.04 0.01-7.78 0.236 Age, years 0.92 0.82-1.02 0.098 1.04 0.94-1.15 0.464 ASA score, > 3 vs ≤ 3 5.39 0.49-59.87 0.170 0.31 0.01-8.18 0.487 Time on dialysis, years 1.05 0.61-1.82 0.855 1.86 1.18-2.93 0.008 Time on immunosuppression, months 0.98 0.95-1.02 0.322 1.00 0.98-1.02 0.862 Histological subtype, non-clear cell vs clear cell 0.605 0.06-6.70 0.682 0.62 0.08-5.06 0.658 T stage, ≥ T1b vs T1a 5.78 0.52-63.78 0.152 0.50 0.01-44.35 0.762 ISUP Grade, G3-4 vs G1-2 2.03 0.18-22.58 0.564 0.55 0.02-14.55 0.718 Size, mm 1.03 0.98-1.08 0.276 1.00 0.92-1.08 0.945 ASA = American Society of Anesthesiologists; CI = confidence interval; ISUP = International Society of Urological Pathology; OS = Overall survival; RFS = Recurrence-free survival. P values < 0.05 are shown in bold type. Archivio Italiano di Urologia e Andrologia 2023; 95, 1 Renal cell carcinoma and transplantation outcome. TNM stage and grade were the only predictors of worse survival. A recent systematic review aimed to compare oncological outcomes of urological cancer in patients who subsequently received a kidney transplant or remained on dialysis (20). For RCC of native kidneys, RFS, CSS and OS were similar between groups, with most of recurrences occurring in the contralateral kidney with- out impact on survival. The main prognostic factors for recurrence were stage, grade and histological subtype, with the authors concluding that immunosuppression didn’t modify the natural history of RCC. In our cohort, no metastasis (apart from recurrences in the contralateral kidney) or cancer-related deaths occurred, precluding any conclusion about these oncological out- comes. This contrasts with most of previous studies and could be related to the fact that only patients with local- ized disease with more favourable prognosis were includ- ed. However, in our opinion, a reduction or even elimina- tion of waiting period would only be feasible in these low- stage cancers, making assumptions more reliable. For high-risk RCC, we believe that a waiting period according to the Cincinnati Registry is still adequate due to the con- siderable risks of recurrence and progression. Several studies have highlighted the distinctive clinical and pathological features of RCC in ESRD comparing to sporadic RCC (19, 21, 22). In line with these reports, we have also found that RCC occurred mainly in young male patients, were generally small and had low stage and grade, with a high incidence of multifocality and bilater- ality. We found a higher incidence of papillary subtype compared to the general population and a substantial prevalence of ccpRCC. ccpRCC is a new but rare entity, first listed in the WHO 2016 renal tumor classification, that has an indolent course with no cases of metastasis reported to date (23). Although also occurring in non- ESRD patients, it is speculated that its prevalence is increased in dialyzed patients. Although RCC of native kidneys of ESRD patients seem to exhibit more favourable pathological and outcome features, the exact reason for its less aggressive behaviour still has to be determined. Possible reasons for this better prognosis include a spe- cific molecular pathway related to ACKD not yet identi- fied, or an earlier diagnosis due to more frequent imaging than the general population. There are no high-level evidence-based recommendations regarding screening for RCC in ESRD patients, and no prospective studies on the cost-effectiveness of this approach. Due to the higher incidence of RCC in this population and the fact that this risk increases with dura- tion of dialysis, several authors have advocated regular screening in pretransplant and post-renal transplant recipients (19, 20, 24). In line with these studies, we also believe that regular screening of native kidneys should be part of pretransplant evaluation in order to diagnose RCC at lower stage and grade, allowing the feasibility of a shorter waiting period for renal transplantation. We acknowledge several limitations in our study. First, in line with previous reports, we recognize that our study is limited by its observational design and that the results should be interpreted within the limits of retrospective data. Although it is unlikely that randomised controlled trials will be conducted in this setting due to ethical and logistical difficulties, well-designed prospective cohort studies are needed to confirm the safety of a reduced waiting period. Second, this was a single-center study with a small sample size, which only included patients with localized disease. However, in order to evaluate the safety of reducing the waiting period for transplantation, we felt that it would be more appropriate to exclude patients with regional nodal or distant metastasis, as these are high-risk patients for recurrence or progressive dis- ease even in the absence of immunosuppression, making comparisons more homogeneous and reliable. Nevertheless, it precluded any conclusion on the effect of immunosuppression in pN+ and/or M+ patients. Third, the low number of events in our cohort may have ham- pered our survival estimates and precluded further analy- sis on CSS. On the other hand, this low number reflects the favourable prognosis that most of these indolent tumors have. CONCLUSIONS Our study shows that most RCCs in native kidneys of renal transplant and dialyzed patients are incidental low- grade and low-stage cancers. These tumors exhibit many favourable clinical, pathological and outcomes features. 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Correspondence Jorge Correia MD (Corresponding Author) jorgericardocorreia@gmail.com Bernardo Teixeira, MD bernardolat@gmail.com Gonçalo Mendes, MD goncalo.grilomendes@gmail.com Avelino Fraga, MD avfraga@gmail.com Miguel Silva-Ramos, MD miguelsilvaramos@gmail.com Department of Urology, Centro Hospitalar Universitário do Porto Largo do Prof. Abel Salazar, 4099-001 Porto, Portugal Conflict of interest: The authors declare no potential conflict of interest.