www.oncotarget.com Oncotarget, 2019, Vol. 10, (No. 33), pp: 3114-3128 Research Paper Gender differences in cancer risk after kidney transplantation Anna Buxeda1, Dolores Redondo-Pachón1, María José Pérez-Sáez1, Álvaro Bartolomé2,3, Marisa Mir1, Ana Pascual-Dapena2,3, Anna Sans2,3, Xavier Duran4, Marta Crespo1,2 and Julio Pascual1,2 1 Department of Nephrology, Hospital del Mar, Barcelona, Spain 2 Department of Medicine, University Autonoma Barcelona, Barcelona, Spain 3 Department of Experimental and Health Sciences, University Pompeu-Fabra, Barcelona, Spain 4 Methodology and Biostatistics Support Unit, Institute Hospital del Mar for Medical Research (IMIM), Barcelona, Spain Correspondence to: Julio Pascual, email: julpascual@gmail.com Keywords: cancer; immunosuppression; kidney transplant; gender; risk factor Received: November 22, 2018     Accepted: March 23, 2019     Published: May 03, 2019 Copyright: Buxeda et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Kidney transplant (KT) recipients are at greater risk of developing some cancers than the general population. Moreover, cancer is the only cause of death that is currently increasing after kidney transplantation. We analyzed incidence, risk factors and characteristics of post-transplant malignancies (solid organ tumors and lymphoproliferative disorders) at our center in 925 KT recipients (1979-2014). Sex differences were particularly assessed. One hundred and eight patients (11.7%) developed solid organ tumors (76.9%) or lymphoma (23.1%). Twenty-one percent of patients who reached 20 years after KT developed cancer, with a median post-KT time to diagnosis of 7.4 years. Most common solid organs affected were lung (30.1%), prostate (10.8%), bladder (9.6%), and native kidney (7.2%). When analyzing standardized incidence ratios (SIR) by gender compared to the general population, relative risk was increased in women (SIR = 1.81; 95%CI, 1.28–2.45) but not significantly increased in men (SIR = 1.22; 0.95–2.52). Regarding specific types, gynecological (SIR = 11.6; 4.2–22.7) and lung (SIR = 10.0; 4.3–18.2) in women, and bladder (SIR = 16.3; 5.9–32.1) in men were the most affected locations. Thymoglobulin, a polyclonal antibody that has been used as an immunosuppressive agent in kidney transplantation over the last decades, was a significant risk factor for developing cancer in adjusted regression analysis [IRR = 1.62, 1.02–2.57; p = 0.041], and was associated with lower patient survival. Compared with the general population, the incidence of post-KT non-skin cancer is almost two-fold higher in women but not significantly higher in men. Lung is the most common solid organ affected. Thymoglobulin induction therapy is associated with a greater risk. INTRODUCTION of cancer has been reported in this population [4, 5]. Moreover, the outcomes and prognosis of KT patients with In patients with end-stage kidney disease (ESKD) some cancers are substantially worse than in those patients and requirement of renal replacement therapy, kidney with cancer but without kidney disease [6–8]. transplantation (KT) is preferred over dialysis as it The cumulative incidence of de novo cancer after provides both improved patient survival and quality of transplantation is 9–10% at 10 years and between 10–27% life at lower costs [1–3]. However, an increased incidence at 20 years, excluding non-melanoma skin cancer [3, 9–11]. www.oncotarget.com 3114 Oncotarget The importance of cancer in KT relies on its impact on in southern European transplanted patients (mostly patient survival, being the second long-term cause of death in reported in Italian population) [31]. No data is available in KT patients [12]. In fact, cancer after KT is the only cause of Spainish renal transplant population, the country with the death that is currently increasing [13]. Immunosuppression highest rate of KT per million population. causes a substantial increase in cancer risk [14, 15]. The aim of our study was to analyze the incidence of Age and male sex are recognized risk factors cancer in our cohort of KT recipients and compare it with associated with the development of malignancy after KT general population, as well as to study the characteristics [4]. Other factors have been described: underlying kidney and risk factors of post-transplant malignancies (PTM). disease, type of donor (deceased and expanded donor are Donor characteristics, recipient’s medical history at substantially increased risk of cancer compared with and immunosuppression regimens were evaluated. In living donor) [16], cancer before transplant [17, 18], particular, a gender effect was assessed. oncogenic viruses such as human papillomavirus (HPV) or Epstein-Barr virus (EBV) [19], acute rejection (AR) RESULTS [20], race [21] or tobacco [22]. However, the literature on this subject is heterogeneous and except for cancers Prevalence of cancer and distribution associated with lifestyle factors like tobacco or caused by viral infections, most of these risk factors have not been During the observation period (May 1979 to April related to a specific cancer location. 2016), from a total of 925 KT recipients, 108 (11.7%) In addition, overall immunosuppressive dose is developed at least one cancer. Eighty-three patients associated with an increased risk of cancer following (76.8%) had at least one solid organ tumor, and 25 transplantation. Immunosuppression may facilitate patients (23.1%) had a lymphoproliferative disorder. carcinogenesis by decreasing mechanisms involved in One patient had both entities (solid organ tumor and a the immunologic control of oncogenic viral infection lymphoproliferative disorder). (Figure 1). and cancer immunosurveillance or by direct DNA Lung cancer was the most frequently observed, damage [12]. Currently available immunosuppressive accounting for 30.1% of all solid organ cancers in our therapies influence different anti-cancer pathways, cohort, followed by prostate (10.8%), urinary bladder but the contributive effect of each agent is not well (9.6%), native kidney (7.2%) and gynecological tumors established at this moment [23]. T cell-depleting agents, (7.2%). The distribution of solid organ cancers is shown such as thymoglobulin, are widely used as induction in Figure 2. immunosuppressive therapy and to treat rejection in KT Median post-KT time to cancer diagnosis was 7.4 recipients. Earlier studies have demonstrated that the years (IQR 3.2-9.7), with an overall cumulative incidence use of T cell-depleting antibodies is associated with an of PTM at 20 years after transplantation of 20.7%. increased risk for post-transplantation lymphoproliferative (Figure 3). disorders (PTLD) compared to interleukin-2 receptor alpha chain (IL-2Ra) agents or no induction therapy [24, 25]. On Estimation of cancer risk in KT compared to the the other hand, mammalian target of rapamycin inhibitors risk in the general population (mTORi) have been reported to inhibit cancer progression in animals and to be associated with reduced incidence Based on these data, we determined that the of posttransplant de novo malignancies in humans [26]. estimated incidence rate of PTM in our cohort was 1536 Nonetheless, authors have not been able to demonstrate cases per 100,000 inhabitants/year. This was higher than improved survival in KT recipients taking mTORi [27]. in general population in Catalonia, where the estimated The increased risk of post-KT malignancy is not incidence rate for malignancies (excluding non-melanoma spread evenly over all types of cancer [24]. Certain skin cancer) is 393.4 cases per 100,000 inhabitants/year malignancies, such as lung, liver and kidney cancer, for women and 557.6 cases per 100,000 inhabitants/year melanoma and non-melanoma skin cancer, PTLD, for men [32] (Figure 4). Relative risks of non-skin cancers and thyroid cancer, are increased. Furthermore, risk is compared to the general population in Catalonia were particularly high for malignancies caused by viral infections, expressed as age standardized incidence ratios (SIRs). including anogenital cancers (human papillomavirus), non- When analyzing SIRs computed using sex of overall PTM Hodgkin lymphoma and Hodgkin lymphoma (both due to compared to the general population in Catalonia, relative EBV), Kaposi sarcoma (human herpes virus 8) and liver risk was increased in women (SIR = 1.81; 95% CI, 1.28– cancer (hepatitis C and B viruses) [4, 9, 14, 23]. 2.45) but not significantly increased in men (SIR = 1.22; Several population-registries have analyzed the 95% CI, 0.95–2.52). Nevertheless, in both sexes a wide incidence of cancer after KT in the United States [4], range of malignancy types had more pronounced risk Australia and New Zealand [10], Europe [28] and Asia comparing with the general population. The locations [29, 30]. Nevertheless, there is little evidence in the with greatest risk were: gynecological (SIR = 11.59; literature about incidence, risk factors and cancer location 95% CI, 4.17–22.71), lung cancers (SIR = 10.05; 95% www.oncotarget.com 3115 Oncotarget CI, 4.29–18.22) and PTLD (SIR = 5.95; 95% CI, 2.54– time of transplantation was 47.9 years (SD 14.2 years). 10.79) in women, and bladder (SIR = 16.35; 95% CI, The majority of recipients were male (62.8%) and 5.88–32.05), PTLD (SIR = 5.54; 95% CI, 3.22–8.49) and Caucasian (93.3%). The most frequent primary renal native kidney cancers (SIR = 4.48; 95% CI, 1.78–8.41) in disease was glomerulonephritis (n = 217, 24.4%), men. On the contrary, the relative risk of malignancy types followed by polycystic kidney disease (n = 120, 13.5%). occurring most frequently in general population was only 87.7% of recipients were on hemodialysis before KT moderately elevated or not elevated, e.g., breast, prostate and, on average, they spent 22 months (IQR 11–41) on and colorectal. (Table 1). dialysis prior to KT. Kidney donors were predominantly male (57.9%), Caucasian (95.2%), and with a mean age Basal characteristics and risk factors of 46.9 (± 16.3) years-old. Induction immunosuppressive treatment was based on anti-CD25 drugs in 49.9% of Baseline characteristics of recipients, donors, cases, and only 22.8% of recipients received T-cell and KT are shown in Table 2. Mean recipient age at depleting agents. The most common maintenance Figure 1: Patients flow-chart. Abbreviations: KT: Kidney transplant, SOC: Solid organ cancer, PTLD: Post-transplantation lymphoproliferative disorders. www.oncotarget.com 3116 Oncotarget Figure 2: Post-transplant solid organ cancer distribution. Graph shows the spectrum of malignancies after kidney transplantation (number of cases). Figure 3: Cumulative incidence of post-transplant malignancies. Cumulative incidence of post-transplant malignancies after kidney transplantation, according to time since transplant. www.oncotarget.com 3117 Oncotarget immunosuppressive regimen consisted of prednisone, (IRR) 1.62 (95%CI, 1.02–2.57), p = 0.041). The association calcineurin inhibitors and mycophenolic acid. between cancer and maintenance immunosuppression No differences were found among recipients with with cyclosporine vs Tacrolimus or MMF was lost after and without cancer in terms of age at transplantation, sex, adjustment for covariates (recipient age, type of donor and cause of ESKD, pre-transplant malignancy, previous KT, thymoglobulin induction). (Table 3). type of renal replacement therapy (RRT), time on RRT, On the other hand, the number of patients treated donor characteristics between groups, biopsy proven with thymoglobulin was similar between those who AR, CMV infection and BK virus. Likewise, initial and developed PTLD and solid organ cancer (36.4% vs 33.8% one-year treatment after transplantation with calcineurin respectively, p = 0.823). inhibitors or mTORi showed no association with PTM development. Survival analysis In the univariate analysis, recipient´s Caucasian race (92.5% vs 99.1%, p = 0.011), thymoglobulin induction (34% Kaplan Meier analysis showed that patients with vs 21.3%, p = 0.005), maintenance immunosuppression PTM had lower survival rates compared to patients who with cyclosporine vs tacrolimus (55.3% vs 38.3%, did not develop cancer at the end of follow-up. Ten-year p = 0.002) and treatment with mycophenolate mofetil patient survival was 89.8% in those recipients without (MMF) 1 year after-KT (60.8% vs 50%, p = 0.036) were cancer vs 10.7% in those patients who developed cancer significantly associated with the development of cancer (p<0.001). (Figure 5A). Death-censored graft survival after transplantation. (Table 2). analysis (grafts lost not due to patient death) did not show However, Poisson Regression analysis confirmed statistically significant differences between patients with that only thymoglobulin induction was an independent risk PTM and those who did not develop cancer at 10 years of factor for post-KT cancer diagnosis [Incidence Rate Ratio follow up (62.1% vs 68.3, p<0.001). (Figure 5B). Figure 4: Estimated incidence of post-transplant malignancies (PTM) compared to general population in Catalonia. Comparison of estimated incidence rates of PTM between our cohort (1536 cases per 100,000 inhabitants/year) and the general population in Catalonia (393.4 cases per 100,000 inhabitants/year for women and 557.6 cases per 100,000 inhabitants/year for men). Abbreviations: KT: Kidney transplant, M: Men, W: Women. www.oncotarget.com 3118 Oncotarget Table 1: Standardized incidence ratios by specific cancer types and gender Women Men Organ Location Number of cases at SIR (95% CI) Number of cases at SIR (95% CI) sample sample Lung 8 10.05 (4.29 - 18.22) 17 2.22 (1.29 - 3.4) Bladder 2 5.76 (0.54 - 16.51) 6 16.35 (5.88 - 32.05) PTLD 8 5.95 (2.54 - 10.79) 17 5.54 (3.22 - 8.49) Gynecological 6 11.59 (4.17 - 22.71) - - Kidney 2 4.98 (0.47 - 14.29) 7 4.48 (1.78 - 8.41) Oral Cavity 2 8.24 (0.78 - 23.61) 3 1.6 (0.3 - 3.91) Stomach 0 - 4 2.78 (0.72 - 6.18) Colorectal 2 0.72 (0.07 - 2.05) 3 0.4 (0.08 - 0.98) Liver 1 3.62 (0 - 14.19) 2 1.33 (0.13 - 3.82) Pancreas 1 1.92 (0 - 7.52) 1 0.83 (0 - 3.25) Breast 4 0.85 (0.22 - 1.88) 0 - Prostate - - 9 0.77 (0.35 - 1.35) Brain 0 - 1 1.48 (0 - 5.8) Thyroid 1 2.86 (0 - 11.2) 0 - Eye 0 - 1 0.06 (0 - 0.25) All cancers 37 1.81 (1.28 - 2.45) 71 1.22 (0.95 - 1.52) Standardized incidence ratios (SIRs) and 95% confidence intervals for most common de novo malignancies according to sex compared to the general population in Catalonia. Abbreviations: PTLD: Post-transplant lymphoproliferative disorder. DISCUSSION increased compared to general population with a SIR of 1.81 in women and a non-significant 1.22 in men. These This retrospective study analyzed the incidence and rates were lower than the ones described in previous risk factors of cancer in a cohort of 925 KT recipients. studies with an incidence of cancer among KT recipients The main finding is that the true increase in cancer in KT two to four-fold higher than those age and sex-matched compared with the general population occurs mostly in individuals from general population [4, 14, 28–30, 35]. women. We observed an incidence of 11.7% PTM, with Despite that apparent difference with the previously an overall cumulative incidence that reached 20.7% of published data, our results are quite similar to those found patients at 20 years. Lung was the most common solid in the European population [28, 31]. organ affected. Compared with the general population, the As we previously mentioned, cancer locations in greatest increase was seen in gynecological malignancies, KT patients differ from malignancy types occurring most lung cancer and PTLD in women; and bladder, PTLD and frequently in general population (e.g., breast, prostate kidney cancer in men. Cancer conferred lower patient and colorectal). The most affected cancer locations in survival and only thymoglobulin was an independent risk Catalonia [32] and Hospital del Mar [36] are prostate, factor for PTM diagnosis. colorectal, breast and lung. When analyzing organ The increased incidence of cancer in KT recipients location affected in our cohort, PTLD, lung, prostate is well established [4, 11, 14, 28-31, 33]. Previous series and bladder were the most frequent PTM, although the and reports have described that cumulative incidence greatest increase in PTM incidence among KT recipients of solid organ cancers after KT increases from 4–5% at compared with the general population was seen in 5 years to 10% at 10 years and to >25% after 20 years gynecological malignancies, lung cancer and PTLD in of KT, similar to our results [9-11, 34]. As expected, women; and bladder, PTLD and kidney cancer in men. the incidence of cancer after KT in our cohort was also Interestingly, this cancer distribution was slightly different www.oncotarget.com 3119 Oncotarget Table 2: Univariate analysis comparing KT recipients with and without solid organ cancer or lymphoma ALL WITHOUT cancer WITH cancer p- Value (n=925) (n=817) (n=108) Basal characteristics Recipient age (years, mean ± 47.9 ± 14.2 47.8 ±14.4 48.32 ± 13 0.765 SD) Sex Female (n, %) 345 (37.2) 308 (37.6) 37 (34.3) 0.499 Caucasian race (n, %) 857 (93.3) 751 (92.5) 106 (99.1) 0.011 Arterial hypertension (n, %) 744 (81%) 663 (81.8%) 81 (75%) 0.194 Diabetes mellitus (n, %) 115 (12.5%) 106 (13%) 9 (8.3%) 0.166 Primary kidney disease: PKD 120 (13.5) 99 (12.7) 21 (29.4) 0.054 vs. others (n, %) Pre-KT cancer (n, %) 42 (4.5) 36 (4.4) 6 (5.6) 0.590 Previous transplant (n, %) 131 (14.2) 117 (14.3) 14 (13) 0.704 RRT before KT (n, %) 0.088 None 19 (2.1) 19 (2.4) 0 (0) HD 131 (14.2) 694 (86.9) 101 (94.4) PD 87 (9.6) 82 (10.3) 5 (4.7) KT 5 (0.6) 4 (0.5) 1 (0.9) Time in RRT (months, median 22 [11–41] 22 [11–40] 23 [11–41] 0.925 [IQR]) Type of donor (n, %) 0.059 Standard criteria donor 550 (60.4) 476 (59.2) 74 (69.8) Expanded criteria donor 258 (28.4) 232 (28.9) 26 (24.5) Living donor 102 (11.2) 96 (11.9) 6 (5.7) Donor age (years, mean ± SD) 46.9 ± 16.3 47.3 ±16.3 43.9 ± 16.2 0.034 Donor sex female (n, %) 371 (42.1) 331 (42.5) 40 (38.8) 0.474 Donor Caucasian race (n, %) 793 (95.2) 703 (95.1) 90 (95.7) 0.792 Initial immunosuppression Thymoglobulin induction (n, %) 185 (22.8) 152 (21.3) 33 (34) 0.005 Calcineurin inhibitor (n, %) 788 (94.5) 695 (94.6) 93 (93.9) 0.800 Mycophenolate (n, %) 589 (64.2) 529 (65.2) 60 (56.1) 0.063 mTOR inhibitor (n, %) 21 (2.3) 20 (2.5) 1 (0.9) 0.319 1 year afterKT immunosuppression Calcineurin inhibitor (n, %) 778 (91.8) 682 (91.7) 96 (92.3) 0.824 Tacrolimus levels (ng/ml, mean 8.2 ± 3 8.1 ± 3 9 ± 3.1 0.156 ± SD) Cyclosporine levels (ng/ml, 212 [176–322] 214 [177–344] 208.5 [175–252] 0.678 median [IQR]) Tacrolimus use (n, %) 470 (60.4) 422 (61.9) 48 (50) 0.026 www.oncotarget.com 3120 Oncotarget ALL WITHOUT cancer WITH cancer p- Value (n=925) (n=817) (n=108) Basal characteristics Mycophenolic acid derivatives 503 (59.5) 451 (60.8) 52 (50) 0.036 use (n, %) mTOR inhibitor use (n, %) 54 (6.4) 51 (6.9) 3 (2.9) 0.120 Follow-up Biopsy proven acute rejection 130 (14) 117 (14.3) 13 (12) 0.527 (n, %) CMV infection (n, %) 125 (13.8) 108 (13.5) 17 (16) 0.477 BK virus (n, %) 25 (3.3) 23 (3.4) 2 (2.4) 0.616 Abbreviations: SD: Standard deviation, PKD: Polycystic kidney disease, KT: Kidney transplantation, RRT: Renal replacement therapy, HD: Hemodialysis, PD: Peritoneal dialysis, IQR: Interquartile range, mTOR: Mammalian target of rapamycin inhibitor, CMV: Citomegalovirus. Table 3: Multivariate analysis: poisson regression IRR 95% confidence interval p- Value Recipient age 1.014 [0.997 - 1.032] 0.112 Type of donor (living donor 0.360 [0.086 - 1.503] 0.086 vs others) Thymoglobulin induction 1.619 [1.019 - 2.571] 0.041 Tacrolimus vs. Cyclosporine 0.731 [0.409 - 1.307] 0.291 1 year after KT Mycophenolate 1 year after 0.745 [0.427 - 1.298] 0.298 KT Abbreviations: IRR: Incidence rate ratio, KT: Kidney transplant. in comparison with other PTM series and publications in Observational studies and registries analyses which lip, thyroid and liver had relatively higher have shown a great variety of PTM risk factors. Age incidences [4, 35, 37–41]. Although 68% of lung cancers at transplantation confers an increased absolute risk. were in male recipients, when analyzing SIRs computed However, whereas the absolute risk of cancer among KT in our cohort compared to the general population in recipients increases with older age, the higher relative Catalonia, relative risk was more increased in women risk of cancer seems to be greatest in younger transplant (SIR = 10.05 vs 2.22 in men). This could be explained by recipients, which is in part owing to the scarcity of cancer the large difference in lung cancer rates among men and in the general population at younger ages [34, 40, 44]. women in the Catalan population, where men presented Similarly, it has been described up to 20-30% higher with significant higher rates than women (82.8 vs 17.6 risk of cancer for male and white ethnicity transplant per 100,000 inhabitants-year, respectively) compared to recipients [4, 5, 21]. However, several studies comparing other registries where lung cancer incidence was not that sex differences in PTM rates do not confirm this data [11, different between sexes [42]. In our cohort, eight women 43–45]. A recent multicenter study of 262 female kidney had lung cancer: 6 of them were former or active smokers graft recipients in Vienna reported that 12.2% developed and one was diagnosed early post-transplant (probably PTM within the first 8.4 years after KT, similar incidence not related to immunosuppression). Previous authors have to the one reported in the majority of the studies that also described a more significant increased risk of lung usually include men [46]. In agreement with our findings, cancer in female transplant recipients compared to male two studies have described a higher risk of cancer between recipients [43]. female KT recipients than men. Kim et al.[43] reported www.oncotarget.com 3121 Oncotarget Figure 5: Patient (A) and Graft (B) survival in patients with and without solid organ cancer or lymphoma. (A) Kaplan– Meier curve shows twenty-year death-censored graft survival of kidney transplantation patients with and without cancer. (B) Kaplan–Meier curve shows twenty-year mortality rates of kidney transplantation patients with and without cancer. www.oncotarget.com 3122 Oncotarget a higher age-standardized SIR for all cancers in female of PTM [23]. In our study thymoglobulin induction was an recipients (SIR = 1.9 vs 1.6 in men). Webster et al.[44] independent risk factor for cancer. In fact, it was related found a strong likelihood that women would be diagnosed to a 62% increased risk of having a new cancer diagnoses with a cancer if got a KT before the age of 45 compared compared with those patients who did not received the to men (males vs. females <45 years HR 0.76). Probably, drug, although it was not relate to any specific cancer the role of virus-related gynecological neoplasms might location. influence this increased risk in women. It is far known that In terms of maintenance immunosuppression, KT recipients have a high risk to develop virus-associated Gallagher et al.[3] found no differences when analyzing cancers such as HPV related anogenital ones. Female overall cumulative incidence of non-skin cancer 20 recipients have 14-fold increased risk of cervical cancer, years after transplantation between three different up to 50-fold of vulvar cancer and up to 100-fold of anal immunosuppression strategies: azathioprine and cancer [47–50]. Epidemiological studies often suffer prednisolone, cyclosporine monotherapy, or cyclosporine from underreporting of events, which typically leads to monotherapy followed by a switch to azathioprine and an underestimation. However, in our cohort women had prednisolone after 3 months. Nevertheless, a dose- been followed-up very closely and including regular dependent effect of cyclosporine on cancer development gynecologic visits in addition to the routine follow-up was demonstrated in a study using cyclosporine as visits due to KT. Catalan female KT recipients have up maintenance immunosuppression [57] On the other to 11 times more risk of having a gynecological cancer hand, mTORi have previously demonstrated to inhibit than general population women counterparts. This risk, rather than promote cancer in experimental models and together with 10-fold increase in lung cancer probably to be associated with reduced incidence of posttransplant explain the higher global SIR in women female patients de novo malignancies in human in previous studies [26, compared to men that we found in our cohort. 27, 58–60]. Recent studies and reviews [61, 62] have Other key risk factors for the development of cancer suggested no association between the drug itself and risk after-KT would be time on dialysis before transplantation, of cancer development and all-cause mortality in KT donor characteristics, having a previous KT or pre- recipients. Our results showed an increased risk of cancer transplant cancer history, immunosuppression treatment, with cyclosporine vs tacrolimus and MMF treatment biopsy proven AR and other immunological factors, 1 year after-KT. However, this association was lost after smoking or alcohol use and oncogenic viruses [5, 16, adjustment for covariates. 17, 19, 20, 22, 44, 51]. On the contrary, KT recipients All these data suggest that no immunosuppressive with diabetes mellitus seem to have a 20–30% lower treatment strategies have been proved to reduce non- risk of cancer in the USA, Australia and New Zealand skin PTM risk. This entails an arduous decision for the [5, 44]. Polycystic kidney disease (PKD) has also been nephrologist when choosing the best immunosuppression related to a lower incidence of cancer compared to therapy, especially in those patients with high risk of other causes of ESKD in KT patients [52]. We found cancer. no differences between groups in terms of recipient and Additionally, based on our findings and previous donor characteristics, having or not pre-transplant cancer, literature, developing PTM entails a much lower survival previous KT or AR. Unfortunately, some data such as rate in KT recipients compared to patients who did not lifestyle (tobacco, alcohol use, etc) and oncogenic viruses develop cancer. Survival after 10 years of follow-up was like HPV and EBV were not available in our study. 79.1%, lower than those patients without malignancy The increased incidence of cancer in KT recipients after KT. In fact, not only the survival would be poorer is largely attributed to immunosuppression. Prior studies compared to recipients without cancer, but also compared have focused on the relationship between PTM and to those individuals with cancer in general population different immunosuppressive agents, dose regimens [35, 63]. Farrugia et al.[7] recently described the higher and duration of the immunosuppressive therapy [3, 25, malignancy-related mortality rates among KT recipients 53, 54]. The effect of each drug on cancer risk remains versus general population and stratified by age and gender. controversial and the increased risk of cancer may be However, making direct comparisons between transplant mediated by the total burden of immunosuppression more recipients and general population could lead to inaccurate than by the agent itself [3, 55]. However, information data, as adjustments cannot be fully made for certain types on dose and duration of therapy is not complete in most of people that are over-represented in a specific cohort. databases so researchers tend to investigate the relationship Similar findings have been described in other studies: in between PTM and selected immunosuppressive agents a Dutch kidney transplant cohort, malignancies in KT used for induction/maintenance therapy. Some studies have population were more aggressive and developed at a much shown an association of induction immunosuppression later stage than those in patients without transplants. This with T cell-depleting antibodies with an increased risk led to a lower median patient survival after the diagnosis of PTLD and melanoma [23, 25, 56]. In contrast, IL-2Ra of cancer (2.7 years compared to an average survival of induction has not been associated with significant increase recipients without cancer of 8.3 years [p <0.0001]) [64]. www.oncotarget.com 3123 Oncotarget Eventually, ANZDATA registry and other studies [10, 65] immunosuppression. Antitumor surveillance in selected have underlined that one-third of deaths with a functioning patient groups, particularly in women, and further allograft is due to cancer. development of prevention and screening strategies are KT recipients who develop cancer represent a needed to improve transplant outcomes. challenge since they require a more complex therapeutic approach. On one hand, immunosuppressive treatment MATERIALS AND METHODS tends to be minimized due to the diagnosis of malignancy albeit the possibility of rejection. And secondly, these Patients patients may receive less aggressive cancer treatment due to comorbidities. All these elements contribute to worse This retrospective cohort study used clinical and prognosis for many malignancies in immunosuppressed epidemiological information collected among 1038 hosts. individuals who, between 1979 and 2014, underwent Cancer is a major limitation in achieving optimal KT in Hospital del Mar, Barcelona, Spain. Patients with outcomes in organ transplantation. Its incidence is high a follow-up shorter than 90 days after KT (n = 96) and and it entails poorer prognoses. Further development of those who were lost to follow-up (n = 17) were excluded approaches to prevention and screening early detection of from the analysis. The final cohort consisted of 925 KT. malignancy may play an important role in reducing the Median time to follow-up was 8 (interquartile range (IQR) burden of malignancies in KT recipients. Thus, prevention 3.26–11.29) years. of post-transplant malignancy-related morbidity and mortality must be considered a main endpoint in solid Study variables organ transplant programs [38, 39, 66–68]. Clinical guidelines recommend routine cancer screening for all Recorded baseline data included recipient KT patients, but these recommendations are mostly characteristics (age, sex, ethnicity, body mass index, extrapolated from the general population [69, 70]. In fact, cause of ESKD [categorized as diabetic nephropathy, there is sparse evidence to support routine screening, risk glomerulonephritis, PKD, vascular/hypertensive disease, factors management, and interventional therapies for KT interstitial nephropathy, unknown or other], time on patients [71–73]. dialysis before transplant, type of RRT [categorized The strengths of our study included the high as pre-dialysis, hemodialysis, peritoneal dialysis or validity of the cancer diagnoses based on cytological KT]), comorbidities (diabetes, coronary artery disease, and pathological evidence, and the long duration of the peripheral vascular disease, cerebrovascular disease, follow-up that allowed us to detect the late-onset cancers, previous cancer, human immunodeficiency virus, hepatitis increasing the statistical power. Regarding limitations, B virus, hepatitis C virus), and transplant related factors this was a retrospective study and some relevant clinical such as the era of transplantation. information might be limited. Second, the comparison All patients with a clinical diagnosis of cancer after with the general population was taken from data reported KT (solid organ tumors and lymphomas) were considered in the literature (Catalan Registry of Cancer), which may as cases. A cancer diagnosis required documentation of constitute a selection bias. However, both the area and the histopathological evidence. Skin tumors were excluded for time span of the reference population were similar to those the analysis. in our cohort. Moreover, the number of patients in our cohort is not large enough to accurate the estimated risks Statistical analysis of less common cancers. Finally, risk factors of cancers such as lifestyle, smoking and alcohol use, ultraviolet Continuous data were expressed as means ± exposure, skin type, family history or oncogenic viruses standard deviation (SD) or median and IQR according such as HPV or EBV were not recorded in the database. to their distribution. Categorical data were expressed as In summary, the increased incidence of cancer in percentages. Comparisons of baseline characteristics KT when compared with the general population occurs between recipients with and without cancer were made mostly in women. Lung is the most common solid using Chi2 or Fisher's exact tests to analyze categorical organ affected, accounting for 30% of all solid organ variables, Student's T-test for continuous variables cancers in our cohort. Bladder, gynecological and lung with normal distribution, and Mann–Whitney test for cancers had the greatest SIRs compared to the general nonparametric variables. population. More importantly, thymoglobulin could be Risk factors for cancer diagnosis were evaluated a modifiable risk factor. Our findings should stimulate through Poisson Regression model. Cox proportional research into carcinogenic mechanisms associated with hazards models were used to assess death-censored graft organ transplantation. A greater understanding of cancer- loss, uncensored graft loss and all-cause mortality. Death- related incidence and/or mortality risk after KT will censored graft loss was considered from the transplant allow clinicians to tailor modifiable risk factors such as date to the beginning of an alternative RRT (return to www.oncotarget.com 3124 Oncotarget dialysis o re-transplantation). For non-censored for death CONFLICTS OF INTEREST graft survival (uncensored graft loss) time of exposure was considered from the transplant date to the beginning of an The authors declare no conflicts of interest. alternative RRT or death. 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