Native Renal Cysts and Dialysis Duration Are Risk Factors for Renal Cell Carcinoma in Renal Transplant Recipients

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1 American Journal of Transplantation 2011; 11: Wiley Periodicals Inc. C 2010 The Authors Journal compilation C 2010 The American Society of Transplantation and the American Society of Transplant Surgeons doi: /j x Native Renal Cysts and Dialysis Duration Are Risk Factors for Renal Cell Carcinoma in Renal Transplant Recipients A. Goh* and A. Vathsala Department of Renal Medicine, Block 6 Level 6, Singapore General Hospital, Outram Road, Singapore *Corresponding author: Angeline Goh, agohth@gmail.com Urinary tract cancers are the third most common cancers in renal transplant recipients (RTX). This study examined the impact of dialysis duration and native renal cyst(s) (NRC) on renal cell carcinoma (RCC) occurrence among 1036 RTX followed-up from 1995 to July Abdominal ultrasonography was planned within 1-month of transplant, then every 5 years, or 2 years if renal cysts developed. Based on presence and time of development of NRC, RTX were grouped into those with no (No-NRC), new (New-NRC), preexisting (Pre-NRC) and time-indeterminate NRC (TI-NRC). Ten asymptomatic RTX were diagnosed with RCC at a median of 5.8 years posttransplant and had 5-year graft and patient survivals of 90% and 100%, respectively, following appropriate therapy. RCC occurred only in Pre-NRC and TI-NRC who had significantly longer dialysis duration than No- or New-NRC (6.7 ± 3.9 and 3.3 ± 3.2 vs. 2.7 ± 3.1 and 2.6 ± 2.4 years, respectively). These results suggest that NRC and increased dialysis duration are risk factors for RCC posttransplant. Since early treatment of RCC gives excellent outcomes, regular ultrasonography performed within a month of transplantation, then every 5 years for those without cysts and every 2 years for those with cysts for early detection of RCC is recommended. Key words: Post-transplant, renal cell carcinoma, renal cysts Abbreviations: RTX, renal transplant recipients; RCC, renal cell carcinoma; NRC, native renal cysts; No- NRC, no native renal cysts; New-NRC, new native renal cysts; Pre-NRC, preexisting native renal cysts; TI-NRC, time-indeterminate native renal cysts; UTC, urinary tract cancers; ACKD, acquired cystic kidney disease; SGH, Singapore General Hospital; US, ultrasonography; ESRD, end-stage renal disease; CGN, chronic glomerulonephritis; TGF-b, transforming growth factor-b ; VEGF, vascular endothelial growth factor Received 10 July 2010, revised 13 August 2010 and accepted for publication 21 August 2010 Introduction With the advent of modern immunosuppression, shortterm graft and patient outcomes for renal transplantation have improved markedly, with graft and patient survivals at 1 year posttransplantation exceeding 90% and 95% for deceased donor renal transplants (DDRT) and 95% and 98% for live donor transplants, respectively (1). Consequently, long-term complications of transplantation have become increasingly important. From large database registries, cardiovascular disease, malignancies and infections have been reported as the three leading causes of death among renal transplant recipients (RTX), with malignancies contributing to 9 16% of patient deaths. Among nonskin malignancies occurring in RTX reported to the Australia and New Zealand Dialysis and Transplant Registry, urinary tract cancers (UTC, 8.1%) were the third most common malignancy after lymphomas (15%) and colorectal cancers (9.1%) (2). Likewise, in a retrospective analysis of malignancies occurring in RTX on follow-up at the Singapore General Hospital (SGH), skin, oro-respiratory and urogenital cancers comprised 25% each; of the latter, UTC, including renal and transitional cell carcinomas, were the most common urogenital cancers documented (3). Kasiske et al. demonstrated that RTX experienced a 15-fold increase in risk of renal cell carcinoma (RCC) and a threefold increase in risk for bladder carcinoma in comparison to the US general population (4). Postulated risk factors for the increase in malignancy in a transplanted population are immunosuppression-mediated DNA damage, activation of proto-oncogenes and overexpression of growth factors, interference with DNA repair mechanisms and the loss of immune surveillance and activation of viruses. Risk factors for the higher incidence of UTC in a transplant population have not been clearly elucidated; in fact, given the differences in incidence of RCC versus bladder carcinoma in a RTX population, the risk factors for different types of UTC posttransplant are also likely different. For RCC, Schwarz et al. demonstrated an association of its occurrence posttransplant only with acquired cystic kidney disease (ACKD) but not with duration of dialysis (5). On the other hand, both duration of dialysis and ACKD are established risk factors for RCC in a dialysis population. Although the incidence of RCC is significantly higher in a RTX population than in a dialysis 86

2 Risk Factors for Renal Cell Cancer Posttransplant Figure 1: Patient population included in study. Of the 1132 renal transplant recipients (RTX) on follow-up at our center from January 1995 to July 31, 2007, those who had undergone bilateral native nephrectomy pretransplant, had autosomal-dominant polycystic kidney disease, or had no US performed posttransplant, were excluded from this analysis. The remaining 1036 RTX were divided into four groups based on the presence and timing of occurrence of at least a single renal cyst in the native kidneys: namely, those with no native renal cysts (No-NRC), new native renal cysts (New-NRC), preexisting native renal cysts (Pre-NRC) and time-indeterminate native renal cysts (TI-NRC). ADPKD, autosomal-dominant polycystic kidney disease; US = ultrasonography; No-NRC = no native renal cysts; New-NRC; Pre-NRC = preexisting native renal cysts; TI-NRC = time-indeterminate native renal cysts; describes RTX whose first US was performed greater than 6 months posttransplant and whose timing of onset of cysts could not be established. population [1.39-fold from the study by Kasiske et al. (4)], immunosuppression per se has not been shown to have an additive role in the development of RCC in RTX. This study examined the incidence of RCC in the RTX population on follow-up at a single institution and examined its association with duration of dialysis, occurrence of native renal cysts (NRC) and interval posttransplant. Methods The 1132 RTX on follow-up at the SGH between January 1995 and July 2007 were screened for NRC. From 1995, all RTX routinely underwent their first posttransplant abdominal ultrasonography (US) of native and transplant kidneys within 1-month of their transplant, then every 5 years subsequently. Patients with at least one native or transplant renal cyst(s) underwent US every 2 years and suspicious lesions were further investigated with computed tomography and/or magnetic resonance imaging, followed by the appropriate treatment. Patients transplanted prior to 1995, or those transferring from other transplant centers underwent their first US at the earliest opportunity. Patient demographics, clinical characteristics, duration of dialysis pretransplant, presence of NRC on US, timing of occurrence of NRC and follow-up interval posttransplant, were recorded from review of an electronic database and medical records. For all transplants, including re-transplants, duration of dialysis was taken from the date of first dialysis. After excluding RTX with autosomal-dominant polycystic kidney disease and those who had undergone bilateral native nephrectomy pretransplant or had no US performed (Figure 1), 1036 with a minimum follow-up of 6 months posttransplant were included in this analysis. Patients with RCC also had their time to occurrence of cancer, histological diagnosis, cancer grade, treatment and patient outcomes recorded. Outcomes for all patients were analyzed until graft loss, patient death, or till July 31, The study population was evaluated for the presence of risk factors for RCC by examining the presence or absence of NRC, timing of onset of NRC in relation to transplantation, duration of dialysis pretransplant and interval posttransplant. To evaluate these risk factors in the development of RCC posttransplant, RTX were stratified into four groups based on the presence and timing of occurrence of at least a single renal cyst in the native kidneys: namely, those with no native renal cysts (No-NRC), new native renal cysts (New-NRC), preexisting native renal cysts (Pre-NRC) and time-indeterminate native renal cysts (TI-NRC). While No-NRC were RTX who had not developed any NRC during the study period, New-NRC were those who had at least one US posttransplant documenting the absence of cysts, with new cysts having been detected on a subsequent US. RTX with NRC on an US performed pretransplant, or those with NRC present on an US performed within 6 months of the transplant were defined as Pre-NRC. RTX whose first US was performed more than 6 months posttransplant and demonstrated the presence of cysts were designated as TI-NRC as the timing of onset of cysts could not be established. Duration of dialysis and interval posttransplant were compared between groups; the independent impact of these two variables was analyzed by logistic regression analysis using a stepwise model. All data was analyzed using STATA software, version 10.1 (StataCorp., College Station, TX, USA). Parametric and nonparametric analyses were performed as indicated. A p-value of <0.05 was considered significant. This retrospective study was approved by the SGH Institutional Review Board. Results The demographic and clinical characteristics of the 1036 RTX who constituted the study population are listed in Table 1. The majority were Chinese males who had received DDRT and the most common etiology of endstage renal disease (ESRD) was chronic glomerulonephritis (CGN). The study population had a mean duration of American Journal of Transplantation 2011; 11:

3 Goh and Vathsala Table 1: Characteristics of study population N = 1036 Period of transplant Gender, N (%) Male 568 (54.8) Female 468 (45.2) Race, N (%) Chinese 869 (83.9) Malay 103 (9.9) Indian 43 (4.2) Others 21 (2.0) Donor type, N (%) Deceased donors, Singapore 570 (55.0) Deceased donors, overseas 167 (16.1) Live-related donors 159 (15.4) Live-unrelated donors 140 (13.5) Etiology of end-stage renal disease Chronic glomerulonephritis 726 (70.1) Diabetes mellitus 35 (3.4) Hypertension 18 (1.7) Systemic lupus erythematosus 26 (2.5) Others 51 (4.9) Unknown 180 (17.4) Age at transplant (years) ± 11.0 Duration of dialysis (years) 1,2 3.8 ± 3.7 Interval posttransplant (years) ± Values reported as mean ± standard deviation. 2 Patients who underwent renal transplantation before they required dialysis were considered to have a dialysis duration of zero years. dialysis of 3.8 years and a mean interval posttransplant of 9.4 years. Characteristics of RTX with RCC Of 14 with UTC in the study population, four had transitional cell carcinoma while 10 had RCC, resulting in an overall incidence of RCC of 0.97% (10 of 1036). The majority of RTX with RCC were Chinese males with DDRT whose etiology of ESRD was CGN (Table 2), reflecting similar demographics as our study population. All 10 patients had received a cyclosporin A (CyA)-based immunosuppressive regimen and the majority (90%) had a net reduction in immunosuppression following tumor diagnosis. Of note was that the median interval from transplant to diagnosis of RCC for five RTX with Pre-NRC was 2.1 (range ) years, while that for the remaining five RTX with TI-NRC was 8.9 (range ) years. This difference was not statistically significant likely due to the small numbers. As shown in Table 3, all RCC occurred in RTX with NRC (p = for those with RCC and NRC vs. No-NRC). All RCC in our study population were asymptomatic, having been detected through routine US screening at an early stage of the disease. Laparoscopic nephrectomy was performed for 6 of 10 RCC patients, while the remaining four underwent open radical nephrectomy of the affected kidney. Upon histological examination, the majority of RCC Table 2: Characteristics of renal transplant recipients with renal cell carcinoma (RCC) No RCC RCC (n = 10) (n = 1026) Gender, N (%) Male 7 (70) 561 (54.7) Female 3 (30) 465 (45.3) Age at transplant (years) 48.6 ( ) ± Age at diagnosis (years) 52.0 ( ) 1 NA Race, N (%): Chinese 10 (100) 859 (83.7) Etiology of ESRD, N (%) Chronic glomerulonephritis 9 (90) 717 (69.9) Hypertension 1 (10) 17 (1.7) Donor type, N (%) Deceased donors 6 (60) 731 (71.2) Live donors 4 (40) 295 (28.8) Duration of dialysis (years) 3.9 ( ) ± Interval posttransplant (years) 9.8 ( ) ± Primary IS, N (%) CyA + prednisolone + 3 (30) mycophenolate CyA + prednisolone + 7 (70) azathioprine Net reduction in immunosuppression, N (%) 9 (90) NA Pre-NRC = preexisting native renal cysts; TI-NRC = timeindeterminate native renal cysts. 1 Values reported as median (range). 2 Values reported as mean ± standard deviation. was clear cell carcinoma, while the remainder was of papillary and mixed cell types. Five-year graft and patient survivals were 90% and 100%, respectively. Risk factors for RCC The demographics and clinical characteristics for the four groups, stratified by presence and timing of NRC, are shown in Table 4. The Pre-NRC group was significantly older and included primarily DDRT with a longer Table 3: Tumor characteristics and surgical management of renal cell carcinoma (RCC) RCC (n = 10) Radiological diagnosis, N (%) 10 (100) Native renal cysts, N (%) 10 (100) Tumor type, N(%) Clear cell 6 (60) Papillary cell 2 (20) Mixed cell 2 (20) Tumor size (cm) ( ) UCLA integrated staging system, N (%) Stage I 9 (90) Stage II 1 (10) Surgical procedure performed, N (%) Nephrectomy 10 (100) Laparoscopic 6 (60) Open radical 4 (40) 1 Value reported as median (range). 88 American Journal of Transplantation 2011; 11: 86 92

4 Table 4: Patient characteristics stratified by occurrence of native renal cyst Risk Factors for Renal Cell Cancer Posttransplant No-NRC, New-NRC, Pre-NRC, TI-NRC, N = 392 (37.8%) N = 166 (16.0%) N = 274 (26.5%) N = 204 (19.7%) Period of transplant Gender, N (%) Male 210 (53.6) 87 (52.4) 146 (53.3) 125 (61.3) Female 182 (46.4) 79 (47.6) 128 (46.7) 79 (38.8) Race, N (%) Chinese 314 (80.0) 145 (87.4) 236 (86.5) 174 (85.3) Malay 47 (12.0) 11 (6.6) 27 (9.9) 18 (8.8) Indian 21 (5.4) 5 (3.0) 10 (3.6) 7 (3.4) Others 10 (2.6) 5 (3.0) 1 (0.4) 5 (2.5) Donor type, N (%) Living donors 168 (42.9) 45 (27.1) 33 (12.0) 53 (26.0) Deceased donors 224 (57.1) 121 (72.9) 241 (88.0) 151 (74.0) Etiology of ESRD, N (%) CGN 273 (69.7) 121 (72.9) 198 (72.3) 134 (65.7) DM 14 (3.6) 3 (1.8) 12 (4.4) 6 (2.9) Hypertension 3 (0.8) 3 (1.8) 8 (2.9) 4 (2.0) SLE 8 (2.0) 2 (1.2) 10 (3.6) 6 (2.9) Others 26 (6.6) 3 (1.8) 10 (3.6) 12 (5.9) Unknown 68 (17.3) 34 (20.5) 36 (13.1) 42 (20.6) Age at transplant (years) ± ± ± 9.1 3, ± 9.5 4,7 Number with RCC, N (%) 0 (0) 0 (0) 5 (1.8) 5 (2.5) Duration of dialysis (years) ± ± ± 3.9 3,5 3.3 ± 3.2 4,6,7,8 Interval posttransplant (years) ± ± ± 2.8 3, ± 4.5 4,7,8 Interval from dialysis to cyst formation (years) 1 NA 12.4 ± ± NA Interval from transplant to cyst formation (years) 1 NA 9.8 ± 4.5 NA NA Interval from transplant to new cyst formation (years) 1 NA 2.5 ± 2.1 NA NA No-NRC = no native renal cysts; New-NRC; Pre-NRC = preexisting native renal cysts; TI-NRC = time-indeterminate native renal cysts; ESRF = end-stage renal disease; CGN = chronic glomerulonephritis; DM = diabetes mellitus; SLE = systemic lupus erythematosus; RCC = renal cell carcinoma; IUS per year = immunosuppression unit score. 1 All values are reported as mean ± standard deviation. 2 No-NRC vs. New-NRC, p < No-NRC vs.pre-nrc, p < No-NRC vs. TI-NRC, p < 0.003, Student s t-test. 5 New-NRC vs. Pre-NRC, p < New-NRC vs. TI-NRC, p < Pre-NRC vs. TI-NRC, p < No-NRC vs. New-NRC vs. Pre-NRC vs. TI-NRC, p < (ANOVA). duration of dialysis than the other three groups. Notably, all 10 RTX (100%) with RCC had NRC, with five each from Pre-NRC and TI-NRC groups, respectively. None of the patients from the No-NRC or New-NRC groups developed RCC. The relative risk of developing RCC in RTX with NRC was 1.72-fold [95% confidence interval (CI) ] higher than that in RTX with No-NRC. The other group who developed RCC, namely those with TI-NRC, likewise had a significantly longer duration of dialysis compared to Newand No-NRC. The stepwise regression analysis evaluating the relationship of dialysis duration and interval posttransplant with the occurrence of NRC demonstrated that only dialysis duration was independently associated [odds ratio (OR) 1.2, 95% CI ]. Discussion The present study demonstrates a 0.88% (10 RCC in 1132 RTX) cumulative incidence of RCC in a renal transplant population followed-up for an average interval of 9.4 years posttransplant. This incidence translates to 94 RCC in RTX patient years, a value nearly 17-fold higher than the reported age-standardized incidence of 5.4 kidney cancers in males/year reported by the Singapore Cancer Registry (6). A direct comparison of RCC incidence between the RTX population described herein and the Singapore general population is not ideal, as the cancer incidence for the latter is age standardized, reported by gender and also represents a group whose RCC was detected at a more symptomatic stage. Nevertheless, the male preponderance with RCC in the RTX population is American Journal of Transplantation 2011; 11:

5 Goh and Vathsala similar to that in the general population. Notably, the median age at RCC diagnosis in RTX of 52 years was lower than the mean age at RCC diagnosis of 57 years reported by Li et al. for the Singapore general population (7). All RCCs in our RTX population were detected through screening by routine US and the overall survival was excellent (5-year graft survival of 90%) with graft outcomes similar to that of a RTX population without RCC (8). The 100% 5-year patient survival for RTX with RCC, as presented herein, is likewise similar to the 5-year patient survival of 97% reported for the general population with low-risk RCC (9). Reports of outcomes for RCC in RTX have been suggested to vary based on interval to diagnosis and staging. Whereas Kleim et al. reported 33% mortality for patients with RCC in their series (10), Schwarz et al. reported no mortality for their patients with RCC also detected by US screening (5). Despite the higher incidence of RCC in RTX, no guidelines exist for screening for RCC in this population. In a review of cancer screening guidelines for a renal transplant population, Wong et al. noted the absence of any randomized controlled trial demonstrating the benefit of screening for RCC (11). The data reported herein, especially with the excellent outcomes occurring due to early screening certainly attests to the value of screening with US in RTX. From their review, Wong et al. also questioned the sensitivity of US to identify small lesions. In our series, all RCC were diagnosed by US; none had metastasized at diagnosis and 90% were Stage I at nephrectomy. As with the absence of guidelines on screening for RCC in a RTX population, no guidelines exist regarding the frequency of screening. Doublet et al. recommended three yearly screening based on a need to make an early diagnosisatatumorsizeof<3 cm (12), while Heinz-Peer et al. recommended annual US screening to detect tumors with a growth rate of cm/year (13). At our transplant center, the frequency of screening was stratified based on the presence of NRC; after an initial screen within 1 month of transplant, all RTX with NRC were screened two yearly while the remainder were screened five yearly. RCC occurrence only in patients with NRC, the development of New-NRC in RTX without preexisting NRC at a mean interval of 2.5 years posttransplant and finally RCC occurrence at a median interval of 4 years posttransplant in RTX with NRC all suggest that an initial screen posttransplant followed by two yearly screening for those with NRC would identify the vast majority of RCC in this high risk population. It is noteworthy that only 65 (5.7%) of all RTX on follow-up at our institution did not have a documented US. This data suggests that US screening for NRC and RCC is effective in diagnosing these lesions early and can be implemented with ease in a large prevalent RTX population. A second important finding from our study was the strong association of RCC with NRC; indeed, RCC occurred only in RTX with NRC. There have been considerable differences in findings with regards to this association of RCC with renal cysts in various studies. Whereas studies by Schwarz et al. and Heinz-Peer et al. (5,14) have demonstrated a strong association of RCC with ACKD in RTX, those by Doublet et al. and Chandhoke et al. (12,14) failed to demonstrate any such association. Schwarz et al. further demonstrated an increased prevalence of RCC in RTX with increasingly complex cysts (4.8% in all RTX vs. 19.4% with ACKD and 54.4% in RTX with Bosniak cysts of IIF to III category). One difference between these previous studies and our study is that, in the former, an association of RCC was searched for only in patients with ACKD, namely those with more than three cysts in both kidneys. Given the lack of sensitivity of US for very small cysts, we took the occurrence of even a single cyst into consideration in establishing a correlation of RCC with NRC in the present study. Including all native RCC, the cumulative incidence of RCC was 1.6% in our RTX population with NRC representing a relative risk of 1.72-fold (95% CI ) in RTX with NRC than in those without NRC. The recommendation of increased frequency of US screening to detect RCC early in RTX with even a single NRC, as proposed herein, is supported by this increased occurrence of RCC in this subpopulation. A third important finding from our study is the 62% prevalence of NRC in a RTX population, with 26% preexisting at the time of transplantation. The longer duration of dialysis pretransplant in those with Pre-NRC compared to the overall study population (6.7 vs. 3.8 years) is the likely risk factor for this prevalence. Matson et al. likewise reported a greater than 40% incidence of NRC in 51 patients on dialysis for three or more years (15), confirming the role of uremia in NRC development. Also noteworthy was the development of New-NRC posttransplant in 16% of our study population (New-NRC). Although dialysis duration was shortest in this group, patients with New-NRC had the longest follow-up interval posttransplant. Following transplantation, New-NRC developed at a mean interval of 2.5 years with cysts developing as late as 15.9 years (range ), suggesting that continued screening is necessary posttransplant. RTX whose timing of cyst formation could not be ascertained (TI-NRC) had a similarly long posttransplant follow-up interval (12.5 years) and a significantly longer dialysis duration compared to the New-NRC group (3.3 ± 3.2 vs. 2.6 ± 2.4 years, respectively, p < 0.03), suggesting that in this group, NRC could have developed pre- or posttransplant. Although, TI- NRC, the only other group with RCC, had a shorter posttransplant follow-up interval than New-NRC, the duration of dialysis was longer for TI-NRC in comparison to the New-NRC group. New-NRC may ultimately be at risk for RCC development with continued exposure to high levels of immunosuppression; however, our study was not able to determine this risk as interval of follow-up post NRC development in this group was only about 3 years. 90 American Journal of Transplantation 2011; 11: 86 92

6 Risk Factors for Renal Cell Cancer Posttransplant The development of NRC or ACKD in chronic kidney disease has been hypothesized to be due to the influence of uremia and uremic toxins (16). With chronic renal failure, nephron loss results in compensatory hypertrophy in the remaining nephrons. This is driven by proto-oncogenes and growth factors, which with time, lead to hyperplasia of the epithelial cells in the renal tubules and renal cyst formation. The longer duration of dialysis in RTX with Pre-NRC and TI-NRC certainly supports this hypothesis. However, the continued development of New-NRC indicates that reversal of uremia posttransplant does not arrest the triggers for cyst formation that may have been initiated in the preceding period of dialysis or uremia. Although Ishikawa et al. suggested that the process of NRC formation may cease or regress following renal transplantation with removal of the uremic milieu and consequent reduction in the level of growth factors (17), our findings suggest that despite transplantation, the downstream effects of activated proto-oncogenes leads to continued NRC formation posttransplant. The activation of proto-oncogenes has been implicated in the pathogenesis of RCC (18). Immunosuppression per se may predispose to malignant transformation by further activating proto-oncogenes or preventing their deactivation, despite the reversal of uremia. Calcineurin inhibitors have been shown to promote tumor progression by direct cellular effects through transforming growth factor-b, independent of their effects on the immune system (19). Vascular endothelial growth factor (VEGF) expression has also been shown to be upregulated under the influence of calcineurin inhibitors; Basu et al. have suggested that increased VEGF expression may provide an environment in which microtumors could grow more efficiently due to angiogenesis, with VEGF transcriptional activation being a key component in the progression of CyA-induced posttransplantation cancer (20). Azathioprine has also been reported to increase the susceptibility of DNA to mutagenesis, by diminishing activity of the DNA mismatch repair system (21). In contrast to in vitro studies, clinical studies have not documented an association of RCC with any single immunosuppressant. Although the ANZDATA registry and Kasiske et al. (2, 4) documented a higher incidence of RCC in RTX in comparison to the dialysis population, single center studies by Doublet et al. and Schwarz et al. (5, 25) have not documented an association of any single immunosuppressive agent with occurrence of RCC. The proportion of RTX receiving Mycophenolate analogs and then developing RCC (3 of 407, 0.74%) was not significantly different from that for RTX not receiving these drugs (7 of 629, 1.1%). Although there were no RTX receiving continuous mammalian target of rapamycin (mtor) inhibitor therapy among those who developed RCC, the overall numbers of RTX receiving these agents (n = 101, 9.7%) in our study population was too small for meaningful analysis. In summary, this study demonstrates an incidence of RCC in RTX, which is more than 10-fold greater than that in the general population. The occurrence of NRC that is even a single cyst confers a 1.7-fold higher risk of developing RCC in RTX. Furthermore, NRC development is not arrested posttransplant. The increased risk of RCC in the subgroups with a longer duration of uremia suggests the initial stimulus for NRC development stemming from a period of uremia was not arrested following transplantation. With potent immunosuppression added posttransplant, the risk for hyperplastic renal tubular cells to undergo malignant transformation increases, potentially triggering NRC to develop into RCC, especially in those with preexisting NRC. As the etiology of ESRD in the majority of RTX who developed RCC in our study population was CGN, these findings may not be applicable to RTX with other etiologies of ESRD such as diabetes. However, with the increased waiting time for a renal transplant currently faced by our patients with ESRD, more patients will have developed NRC by the time of transplantation. Our study further advocates for regular monitoring of ESRD patients on the transplant waiting list for occurrence of NRC. Following transplantation, screening should be performed within a month of transplantation, then every 5 years for those without cysts and every 2 years for those with cysts so as to detect RCC early. Acknowledgment The authors would like to acknowledge the assistance of Ms. Lu York Moi in the collation of data on cancers in the renal transplant population at the Singapore General Hospital. Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. References 1. Briggs JD. Causes of death after renal transplantation. Nephrol Dial Transplant 2001; 16: Stewart JH, Buccianti G, Agodoa L et al. Cancers of the kidney and urinary tract in patients on dialysis for end-stage renal disease: Analysis of data from the United States, Europe, and Australia and New Zealand. J Am Soc Nephrol 2003; 14: Zinna S, Vathsala A, Woo KT. Spectrum of malignancies in Asian renal allograft recipients. 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