In kidney transplant recipients, cancer is one of the leading causes of death with a functioning graft beyond the ﬁrst year of kidney transplantation, and malignancies account for 8–10% of all deaths in the USA (2.6 deaths/1000 patient-years) and exceed 30% of deaths in Australia (5/1000 patient-years) in kidney transplant recipients. Patient-, transplant- and medication-related factors contribute to the increased cancer risk following kidney transplantation. While it is well established that the overall immunosuppressive dose is associated with an increased risk for cancer following transplantation, the contributive effect of different immunosuppressive agents is not well established. In this review we will discuss the different risk factors for malignancies after kidney transplantation. Key words: immunosuppression, kidney transplantation, malignancy, risk factor brain and cervical cancer), others are increased substantially Introduction (lung, colon, liver, lymphoma, melanoma and non-melanoma Malignancy is one of the most common causes of death in kid- skin cancer). Cancer-related mortality rates are also higher in ney transplant recipients [1, 2]. In kidney transplant recipients, kidney transplant recipients compared with the general popu- the incidence of cancer is generally increased 2- to 3-fold com- lation . pared with the general population [3, 4]. This increased cancer Patient-, transplant- and medication-related factors contrib- risk is not spread evenly over all types of cancers; while some ute to the increased cancer risk following kidney transplanta- cancer incidences are not increased (breast, prostate, ovarian, tion. Immunosuppression is considered the most important Received: July 12, 2017. Editorial decision: September 15, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact email@example.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/315/4568992 by Ed 'DeepDyve' Gillespie user on 20 June 2018 316 | B. Sprangers et al. risk factor, as it decreases the immunologic control of oncogenic transplant recipients (145 104 cadaveric kidney transplant recip- viral infection and cancer immunosurveillance [4, 6]. Although ients) between 1985 and 2001 were studied . Over the 10- it is accepted that the overall immunosuppressive dose is asso- year observation period, the risk for malignant lymphoma in ciated with the increased cancer risk following transplantation, renal transplant recipients was 11.8-fold higher compared with the contributive effect of different immunosuppressive agents a matched non-transplanted population, and most lymphomas is not well established at this time. Currently available immu- occurred in the first post-transplant year . Recent data sug- nosuppressive agents influence different anticancer pathways gest that from 2005 to 2010, the 5-year incidence of post- and mammalian target of rapamycin (mTOR) inhibitors have transplant lymphoproliferative disease (PTLD) in adult kidney been reported to have a decreased cancer risk compared with transplant recipients has remained stable . There was, how- alternative immunosuppressive therapies. However, recent ever, a substantial decline in PTLD rates for paediatric recipients studies have not been able to demonstrate improved survival in reported in patients transplanted from 2002 to 2012 compared kidney transplant recipients taking mTOR inhibitors. T cell– with those transplanted from 2000 to 2009 . In all groups, depleting agents are very potent immunosuppressive agents PTLD risk was highest in Epstein–Barr virus (EBV)-seronegative used as induction therapy and to treat acute rejection (AR) in recipients . In kidney transplant recipients, there is a slight kidney transplant recipients. While some studies have sug- predilection for the lymphoma to occur in the transplanted kid- gested an association between antibody induction and cancer ney. In addition, central nervous system lymphomas were most after transplantation [7–11], others have failed to demonstrate common after renal transplantation in the CTS . this association [12–15]. On average, the age at diagnosis of post-transplant cancer is 40 years and the time from transplantation is 3–5 years [12, 28, 32]. However, these numbers vary substantially according to the Epidemiology and clinical presentation cancer subtype, with lymphoma and Kaposi sarcoma occurring early after transplantation [30, 33] and epithelial cancers later on Analyses from different registry data estimate the general increase [33, 34]. Although in other types of solid organ transplantation in cancer incidence in kidney transplant recipients to be two- to cancer tends to occur in the transplanted organ, in kidney trans- three-fold compared with the general population [3, 4, 16–25]. plant recipients, kidney cancers almost exclusively occur in the Estimates of cancer incidence obtained from different registries native kidneys  and there is a greater incidence of papillary differ widely, suggesting that data quality is problematic. This was type relative to the general population . Acquired cystic kid- confirmed in a recent study by Yanik et al. , who compared can- ney disease is common in patients with advanced renal failure cer diagnoses collected in the Scientific Registry of Transplant and is associated with the development of kidney cancer [25, 36]. Recipients (SRTR) database with 15 linked cancer registries for col- In dialysis patients, the risks for thyroid cancer, myeloma and orectal, liver, lung, breast, prostate and kidney cancers, melanoma urinary tract cancers are increased, and this is mirrored in kidney and non-Hodgkin lymphoma (NHL). They concluded that SRTR transplant recipients . This parallel between dialysis patients cancer data were strikingly incomplete, as only 36.8% of cancers and kidney transplant recipients does not hold true for all cancer were both registered in the SRTR database and cancer registries, types, as ovarian and prostate cancer were less frequent in kid- whereas 47.5% of cancers were only documented in cancer regis- ney transplant recipients than in the dialysis cohorts . tries and 15.7% were only documented in the SRTR database . The estimated sensitivity for identifying cancer was only 52.5% for the SRTR and 84.3% for cancer registries . Pathogenesis and transplant-specific risk Data from the USA concerning 175 732 solid organ transplant factors recipients (58.4% kidney transplant recipients) during the period 1987–2008 showed that the standardized incidence ratio (SIR) Several factors have been linked to the increased incidence of for cancer overall was 2.1 (95% CI 2.06–2.14) higher compared malignancies among transplant recipients , including age, with the general population, with an excess absolute risk of 719 sun exposure, previous cancer, concomitant viral infection, cancer cases per 100 000 person-years . The majority of the cumulative dose of immunosuppression, type of immunosup- patients included in these studies were kidney transplant recipi- pression, AR and the duration of pre-transplant dialysis (Table 1 ents . It is important to note that this increase is not uniform and Figure 1)[38, 39]. Risk factors for patient death from for all cancer types; some cancers are not increased following cancer include male gender, a history of prior cancer and kidney transplantation, e.g. breast, prostate, ovarian, cervical and immunosuppression and lymphocyte-depleting antibodies . brain cancers [3, 4, 20], and the incidence of breast cancer might even be reduced [3, 28]. In contrast, lymphoma, lung cancer, Donor transmission colon cancer, melanoma and non-melanoma skin cancer and liver cancer are increased 2- to 4-fold. In a study by Engels et al. A variety of donor-transmitted malignancies have been docu- , skin cancer was the most common malignancy in solid organ mented, including melanoma and cancers of the lung, breast, transplant recipients, with a SIR for Kaposi sarcoma and non- colon, rectum and kidney, Kaposi sarcoma and glioblastoma melanoma skin cancer of 61.46 and 13.85, respectively. In addi- multiforme. Donor transmission as a cause of post-transplant tion, the SIRs for non-Hodgkin and Hodgkin lymphoma, liver can- malignancy is a rare but dreaded event, as it might result in cer, gastrointestinal cancer and melanoma were also increased metastatic disease in the transplant recipient [40–47]. Reported . In more recent reports from both the Australia and New transmission rates are <0.03%, but these are likely under- Zealand Dialysis and Transplant Registry (ANZDATA) registry reported and underdiagnosed [41, 48, 49]. The most common  and European and North American registries , excluding transmitted cancer types are renal cancer, lung cancer, mel- non-melanocytic skin cancers, genitourinary tract cancers are anoma and lymphoma [46, 50, 51]. The risk of donor transmis- the most frequent malignancies in renal transplant recipients. sion depends on the type and extent of the original donor In an analysis of the Collaborative Transplant Study (CTS) cancer. A donor history of melanoma, lung carcinoma or chorio- database, the incidence and impact of malignant lymphoma carcinoma seems to be associated with high transmission risk after solid organ transplantation in 195 938 solid organ and death and organs from such donors should not be accepted Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/315/4568992 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Risk factors for post-transplant malignancies | 317 Fig. 1. Cancerogenesis following kidney transplantation (adapted from Riella ). Table 1. Risk factor for post-transplant malignancies post–kidney transplant malignancies [54, 55]. With increasing recipient age, this is an important factor in the overall increas- Patient-related risk factors Recipient age ing incidence of post-transplant cancer in kidney transplant Previous cancer recipients. Time on dialysis before transplantation has also Sun exposure been identified as a risk factor for developing post-transplant Viral infection malignancy. In a study based on the ANZDATA database, Wong Duration of dialysis et al.  reported a linear relationship between the duration of Transplant-related risk factors Donor transmission dialysis and the risk of solid organ cancer after transplantation, Donor type irrespective of recipient age. In a very interesting article, Yanik Rejection et al.  evaluated the incidence of cancer types depending on Medication-related risk factors Net immunosuppression non-renal function interval (time on dialysis either on wait list Induction therapy or after transplant failure) or kidney function interval (time Maintenance therapy with a functioning graft and thus on immunosuppression), applying a linkage between the SRTR and several US cancer registries. While the incidence of infection-related and for transplantation . In contrast, organs from donors with immune-related cancer (Kaposi sarcoma, NHL, lip cancer and renal cell cancer without capsular invasion and central nervous non-epithelial skin cancer) was higher during kidney function system tumours (except medulloblastoma) are acceptable, as intervals, end-stage renal disease (ESRD)-related cancer inci- the risk seems to be low, reflecting the limited metastatic dence (kidney cancer and thyroid cancer) was lower during kid- potential of these tumours [46, 52]. Regarding outcome, early ney function intervals. Every change of status (non-renal donor-transmitted cancer (diagnosed 6 weeks of transplanta- function interval/kidney function interval) was associated with tion) was associated with a better outcome compared with late a changing incidence for NHL, melanoma, lung, pancreatic and donor-transmitted cancer ; 5-year survival was 83% for kid- non-epithelial skin cancers (higher during function intervals) ney recipients with donor-transmitted cancer compared with and kidney and thyroid cancers (higher during non-function 93% for recipients without donor-transmitted cancer (P¼ 0.077) intervals), suggesting potent short-term effects of kidney dys- [50, 51]. Recipients with transmitted renal cancers had the best function and immunosuppression on cancer incidence . outcomes, with >70% 2-year survival post-transplantation , while patients with melanoma and lung cancers had <50% 2- year survival post-transplantation . Previous cancer Donor type A history of cancer prior to kidney transplantation in the recipi- ent increases the risk of death by 30% .These findings were Differences in the type of transplant (living versus deceased) also confirmed in another study showing that kidney transplant have been associated with cancer risk. In a study by Ma et al. recipients with a pre-transplant cancer are 3.7 times more likely , the overall risks for cancer were 1080, 1444 and 2018 per to die of cancer post-transplantation . Acuna et al.  per- 100 000 patient-years for recipients of living donor, standard formed an interesting meta-analysis including 32 cohort studies and expanded criteria deceased donor kidney recipients, on solid organ transplant recipients with a pre-transplant respectively. This increased risk with different donor types was malignancy in remission. They demonstrated that pre-trans- independent of age, sex, and time on dialysis . Recipients of plant malignancy is associated with an increased risk of all- living-donor kidneys had a lower risk of cancer, particularly for cause mortality (pooled hazard ratio 1.51), cancer-specific mor- genitourinary cancer and PTLD . tality (pooled hazard ratio 3.13) and of developing de novo malig- nancies (pooled hazard ratio 1.92) after transplantation Recipient age and time on dialysis compared with solid organ transplant recipients without a pre- Both in paediatric and adult kidney transplant recipients, recipi- transplant malignancy . These studies clearly identify kidney ent age has been identified as an independent risk factor of transplant recipients with pre-transplant cancer as a high-risk Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/315/4568992 by Ed 'DeepDyve' Gillespie user on 20 June 2018 318 | B. Sprangers et al. patient population requiring tailored screening and management Rejection and treatment strategies. As the total dose of immunosuppression is related to the risk of post-transplant malignancy, it is no surprise that rejection epi- Organ predilection sodes and anti-rejection therapy are associated with the risk of post-transplant malignancy, as doses of maintenance immuno- The incidence of specific malignancies varies according to the suppression including calcineurin inhibitors, antimetabolite transplanted organ . While in some types of transplantation and/or corticosteroids are often increased during the treatment (lung and liver), post-transplant malignancies tend to occur in of rejection, thereby contributing to increased T cell dysfunction the transplanted organ, in kidney transplantation this does not . Besides T cell dysfunction, systemic inflammation and appear to be the case (kidney cancer in kidney transplant recipi- concomitant release of cytokines and chemokines may promote ents primarily affects the native kidney) [3, 4, 16–23]. In addi- malignant transformation [94, 95]. In the CTS, anti-rejection tion, other cancer types vary depending on the transplanted therapy with OKT3 or anti-thymocyte globulin (ATG) increased organ. For example, the risk of NHL in lung transplant recipients the overall cancer risk . In a recent analysis of the is doubled compared with kidney, heart or liver transplant . ANZDATA, Lim et al.  studied the risk of incident cancer It is well established that kidney cancer is greatly increased among kidney transplant recipients who have experienced AR, in dialysis patients and kidney transplant recipients [3, 4, 16– stratified by the use of T cell–depleting antibodies. The study 23]. Prolonged time on dialysis has been identified as a risk fac- included 7153 kidney transplant recipients transplanted tor for the development of kidney cancer [59, 60] and the inci- between 1997 and 2009, of which 6.5% developed cancers. The dence of kidney cancer can be as high as 100 times the expected risk for cancer after first kidney transplantation was signifi- incidence [61, 62]. While kidney cancer in native kidneys is fre- cantly higher in patients experiencing AR treated with T cell– quent, cancer in the transplanted kidney is rare. In a European depleting antibodies (adjusted hazard ratio 1.42) compared with retrospective study, 20 patients were identified with kidney kidney transplant recipients not experiencing AR and the excess cancer in the transplanted kidney: 85% were papillary renal cell cancer risk was mainly confined to genitourinary tract cancers carcinoma (RCC) and 15% were clear cell RCC . The tumours . Also, treatment of rejection with high-dose steroids can were small at the time of diagnosis and all patients were man- adversely affect the risk for PTLD . aged with ablation therapy (cryoablation or radiofrequent abla- tion) without a reduction or change in their immunosuppressive therapy . Maintenance immunosuppression Maintenance immunosuppression is essential after kidney Sun exposure transplantation to prevent allograft rejection. Although it is accepted that overall immunosuppression dose is associated In the development of skin cancer, sun exposure is an estab- with an increased cancer risk following transplantation, the lished risk factor [64–66]. The application of sun block and contributive effect of different immunosuppressive agents is administration of nicotinamide have both been demonstrated not established. The mechanisms linking immunosuppression to reduce the incidence of non-melanoma skin cancer [67–70]. dose to the increased incidence of cancer are numerous and include decreased immune surveillance of tumours, decreased Viral infection antiviral responses resulting in a specific increase of virus- At least four viruses are believed to be co-carcinogenic in trans- induced tumours and possibly the direct carcinogenic effect of planted patients: EBV (Hodgkin’s and NHL), human herpesvirus immunosuppressive drugs such as cyclosporine and azathio- 8 (HHV8; Kaposi sarcoma) [71–73], human papillomavirus (HPV; prine (Table 2). cervix, vulva, vagina, anus and some oro-pharynx cancers) and The cumulative immunosuppressive dose (net immunosup- Merkel cell polyomavirus (Merkel cell skin carcinoma). EBV has pressive dose for the entire life) is associated with the risk for conclusively been implicated in the pathogenesis of PTLD fol- cancer post-transplant. For example, patients previously treated lowing kidney transplantation [74, 75] and EBV status is one of with immunosuppression for primary glomerular disease or the most important risk factors for PTLD. More than 50% of for AR  are at higher risk to develop cancer. Hibberd et al.  PTLD cases are EBV related, and EBV mismatch between donor reported an association between pre-transplantation immuno- and recipient (an EBV-negative receptor engrafted with an EBV- suppression and increased risk for four cancer groups: anogenital positive donor) is associated with a 20-fold increased risk for cancer, NHL, breast cancer and urinary tract cancer (excluding PTLD [76–78]. Moreover, primary EBV infection post-transplant kidney). Grulich et al.  analyzed seven studies of people with is a major risk factor for EBV-positive PTLD in early onset PTLD HIV/AIDS (n¼ 444 172) and five of transplant recipients . Additionally, other viruses have been associated with the (n¼ 31 977) for 20 of the 28 types of cancers. A significantly development of cancer, e.g. hepatitis B and C (HBV and HCV; increased cancer incidence was found in both populations, and liver cancer) and BK polyomavirus (urological cancers) [79–87]. most cancers that occurred at increased rates involved oncogenic The central role of the immune system in the control of onco- viruses (e.g. EBV, HHV8, HPV, HBV and HCV). The rates of most genic viruses was emphasized by the findings of Grulich et al. common epithelial cancers (breast or prostate cancer) were not , where a similar increase of virus-associated cancers was increased . The similarity of the pattern of increased risk of observed in solid organ transplant patients and patients with cancer in the two populations suggests that it is immune defi- HIV/AIDS. As far as cytomegalovirus (CMV) and post-transplant ciency rather than other risk factors for cancer that is responsible malignancy are concerned, conflicting results have been for the increased risk. Of note, there were also some discrepan- reported [88–92], so at this time it is not clear whether CMV cies noted, as some cancer types (thyroid, kidney, melanoma and infection is associated with an increased risk of post-transplant bladder cancers) were increased in the transplant population but cancer. A recent study demonstrated that cancer risk after kid- not in the HIV/AIDS cohorts. ney transplantation during childhood is particularly increased Although results suggest that currently available immuno- for virus-related cancers . suppressive agents influence different anticancer pathways Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/315/4568992 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Risk factors for post-transplant malignancies | 319 Table 2. Immunosuppressive drugs and oncogenesis Immunosuppressant agent Method of action Role in carcinogenesis Calcineurin inhibitor Inhibition of IL-2 production Production of TGF-b [98, 99] through binding and inhibition Production of VEGF [98, 100] of cyclophilin (cyclosporine) and Production of interleukin-6 (IL-6) (promotion of EBV-induced B-cell growth) FKBP-12 (tacrolimus),  respectively Promotion of invasive behaviour of non-transformed cells  Reduced ability to repair radiation-induced DNA damage Enhanced apoptotic effects of taxol and IFN-c on human gastric and bladder cancer cells [102, 103] Increased rate of lymfoproliferative disorders in HSV-infected mice  Azathiopurine Inhibition of DNA and RNA synthe- Intercalation at the DNA level, inhibiting repair splicing and eliciting codon sis through incorporation of thi- misreads  opurine analogues Increased development of microsatellite DNA instability  Mycophenolate mofetil Inhibition of inosine monophos- Anti-proliferative effect on leukaemia and solid tumour phate dehydrogenase and de Inhibition of adhesion molecules [107, 108–114] novo purine biosynthesis Suppressed glycosylation and expression of several adhesion molecules [109, 115] Inhibition of adhesion of colon adenocarcinoma cells to endothelial cells  mTOR inhibitors Inhibition of mTOR pathway Direct antitumour effect by inhibition of mTOR pathway [117, 118] Inhibition of angiogenesis Inhibition of p70 S6K: decreasing cancer cell proliferation [119, 120 Inhibition of interleukin-10: decreasing tumour cell JAK/STATs activity  Inhibition of cyclins: blocking cell-cycle activity  Decreased VEGF-A and VEGF-C signalling: impaired tumour angiogenesis [101, 119, 122, 123] Inhibition of growth signals in PTLD-associated EBV B-cell lymphomas  Inhibition of replication of EBV-positive B cells, T cells and NK cells [125, 126] Inhibition of ultraviolet B–induced metalloproteinase activation  , it is not clear whether currently used medications such as plasma cells, which may explain the predisposition to infec- cyclosporine, tacrolimus, azathioprine or mycophenolate are tions and cancer complications associated with the use of these associated with different cancer risks [14, 129–131]. mTOR inhib- agents [138–140]. itors have been reported to have less cancer risk compared with The immunosuppressive potency of OKT3 is greater than alternative immunosuppressive therapies ; however, in a that of polyclonal lymphocyte–depleting agents and the use of recent systematic review, decreased cancer incidence in kidney OKT3 has clearly been associated with an increase in lymphoma transplant recipients treated with mTOR inhibitors did not risk [14, 141–143]. OKT3 is no longer commercially available, but result in improved overall survival . As induction therapy is other forms of induction therapy are still currently in use and concerned, interleukin-2 (IL-2) receptor antagonist (IL-2Ra) from the late 1990s onwards, rabbit ATG (rATG) became the induction does not appear to be associated with an increase in most commonly used polyclonal agent in the USA [144, 145], cancer , whereas some studies find a small increase in can- and later worldwide [146, 107]. cer and cancer death with lymphocyte-depleting antibodies [5, Polyclonal induction therapy: When evaluating the cancer- 134, 135]. Moreover, there appear to be differences in the differ- inducing effect of different types of polyclonal lymphocyte- ent types of lymphocyte-depleting antibodies. depleting agents, the data are limited and hard to interpret. Available registry analyses have often combined all polyclonal Induction therapy lymphocyte-depleting agents into one category and often span Multiple agents have been used as induction therapy at the multiple decades. Combining different types of induction time of kidney transplantation [e.g. OKT3/muromonab, polyclo- agents (e.g. polyclonal induction agents or ATG) is problematic, nal lymphocyte-depleting antibodies, anti-IL-2 receptor (CD25) as there are clear differences in the risk of PTLD associated with antibodies and alemtuzumab (anti-CD52). As both CD4 and different preparations [141, 147]. Furthermore, over time the CD8 T cells are crucial in adaptive antiviral immunity, type of lymphocyte-depleting agent, the average dose of rATG depletion of both populations of T cells with T cell–depleting and the type and dose of concomitant immunosuppressive antibodies would increase the susceptibility of individuals to a agents have changed significantly. During the 1980s and early higher risk of virus-associated diseases . Direct anti- 1990s, OKT3 and non-rATG preparations were most widely used tumour effects have also been attributed to CD4 T helper 1 [144, 145], and this was associated with a marked increase in cells, CD8 cytotoxic T cells and natural killer (NK) cells . the incidence of PTLD [148, 149]. From the late 1990s onwards, Polyclonal T cell–depleting antibodies target a variety of T and rATG became the most commonly used polyclonal agent in the NK cell-derived antigens, including CD2, CD3, CD4, CD8 and USA [144, 145], and later worldwide . Finally, in the 1980s CD16, but also markers expressed by leucocytes, B cells and rATG dosing was markedly higher than it is now (e.g. total dose Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/315/4568992 by Ed 'DeepDyve' Gillespie user on 20 June 2018 320 | B. Sprangers et al. 14 mg/kg versus 6 mg/kg now)  and it has been demon- of secondary cancers (particularly skin cancers) compared with strated that higher rATG dosing is associated with a higher risk normal-dose (150–250 ng/mL) cyclosporine at a median of of PTLD . 66 months follow-up . Some evidence suggested a higher Earlier studies have suggested an association of induction risk for PTLD under tacrolimus versus cyclosporine [169, 170]. therapy with T cell–depleting antibodies with an increased risk However, subsequent analyses by the same group postulated of PTLD. In an analysis of the CTS, the SIR of lymphoma com- that this was the result of a lack of experience with the agent pared with a similar non-transplant population was higher with and overaggressive dosing at the time of introduction of tacroli- T cell–depleting antibody induction as compared with IL-2Ra or mus in clinical practice. Ultimately, reduced tacrolimus trough no induction therapy . Also, a study of the SRTR and the levels led to substantial declines in the risk of PTLD . An United States Renal Data System databases reported similar analysis of the CTS demonstrated that cyclosporine did not con- results (70% increased risk of PTLD in renal transplant recipients fer added risk for the development of NHL compared with aza- receiving monoclonal and/or polyclonal T cell–depleting anti- thioprine/steroid treatment, whereas treatment with FK506 bodies as induction therapy) [10, 14]. Also, an earlier analysis of increased the risk approximately 2-fold . the ANZDATA registry demonstrated that the use of T cell– Azathioprine: The use of azathioprine has long been recog- depleting antibodies (as induction or as treatment for rejection) nized as an a etiologic factor in the development of neoplasia, was associated with a more than two-fold increased risk of especially in the development of late non-melanoma skin early onset NHL after transplantation . Registry database malignancies (particularly squamous cell cancer) [23, 101, 172, studies reported results regarding rATG use and the occurrence 173]. Furthermore, azathioprine is associated with the develop- of PTLD have been mixed. Only three studies looked at rATG ment of myelodysplastic syndrome . specifically and two found an increased risk for PTLD while one Mycophenolate mofetil: Some patient studies have sug- did not [10, 11, 151]. Other registry studies of PTLD risk have gested that the risk of developing malignancies is decreased grouped multiple lymphocyte-depleting induction agents with the use of mycophenolate mofetil [107, 174, 175], while together for the purpose of analysis, in some cases including other studies could not demonstrate a reduction in cancer inci- OKT3 [14, 152–155]. Three prospective randomized trials fol- dence with mycophenolate- versus non-mycophenolate-based lowed patients up to 5 years after kidney transplantation [156– therapy . An SRTR analysis reported that the introduction 158]. The incidence of PTLD and the follow-up time were too of mycophenolate mofetil was associated with the greatest limited to allow for meaningful conclusions [159–162]. Finally, a decrease in relative risk for the development of PTLD . When systematic review by Marks et al.  evaluated the rate of PTLD patient outcomes during different eras of immunosuppression in recipients of kidney or heart allografts and pointed to the were compared, the use of MMF was also found to be associated importance of antiviral prophylaxis, as in this study; the with a reduction in the incidence of PTLD [9, 174, 176]. In absence of antiviral prophylaxis was the greatest risk factor for patients, the principal anti-tumour mechanism associated with the development of PTLD rather than the use of induction mycophenolate mofetil use may be due to the decreased inci- therapy. dence of AR. IL-2R antagonist induction: In the CTS, induction therapy mTOR inhibitors: While for most classes of immunosuppres- with polyclonal and IL-2Ra induction was not associated with sive agents there is a dose-dependent relationship between the significant increases in the risk of PTLD when compared with dosage of the immunosuppressive agent and secondary malig- no induction therapy . However, universal use of IL-2Ra nancies, this does not hold true for mTOR inhibitors such as induction is increasingly questioned, as it does not provide ben- sirolimus and everolimus. In humans, evidence suggests that efit in low-risk kidney transplant recipients compared with no sirolimus may confer a decreased risk of malignancy compared induction therapy, while being inferior compared with ATG in with other immunosuppressive medications [101, 133, 177–181]. high-risk kidney transplant recipients [161, 163–165]. In a recent Case reports and case series have reported that in renal trans- observation study, rATG was associated with a decreased risk of plant recipients with Kaposi sarcoma, switching from cyclo- adverse outcomes (including mortality) compared with alemtu- sporine to sirolimus resulted in total resolution of the Kaposi zumab and basiliximab as induction therapy . sarcoma [179, 182, 183]. In the TUMORAPA study, where patients Alemtuzumab: In the Transplant Cancer Match study, the with a history of squamous cell carcinoma were studied, con- use of alemtuzumab as induction therapy was associated with a version to sirolimus significantly reduced the risk for relapse 79% increase in NHL, a 2.5-fold increase in colorectal cancer and when compared with those who were maintained on 3-fold increase in thyroid cancer after transplantation . calcineurin inhibitor–based therapy . For non-melanoma Other studies have reported mixed results regarding the use of skin cancer, Campbell et al.  reported that conversion to alemtuzumab and PTLD; although one study did not find an sirolimus after 1-year post-transplant resulted in a lower yearly association , another using a more recent Organ incidence rate of non-melanoma skin cancer and also a lower Procurement and Transplantation Network cohort did . A incidence of new or recurrent non-melanoma skin cancer. recent study in small bowel allograft recipients receiving alem- Individual studies regarding the incidence of cancer associated tuzumab demonstrated earlier onset of lymphoplasmacytic with the use of sirolimus have been conflicting [177, 186–193]. In hyperplasia, the most indolent form of B lymphocyte clonal a study linking the US SRTR database with 15 population-based expansion, compared with patients receiving the IL-2Ra induc- cancer registries and national pharmacy claims, cancer inci- tion agent daclizumab . dence in 32 604 sirolimus-exposed and sirolimus non-exposed kidney transplant recipients was studied. The incidence of pros- tate cancer was higher during sirolimus use (hazard ratio 1.86), Maintenance therapy while the incidence of other cancers was similar or lower, with Calcineurin inhibitors: In kidney transplant recipients, both a 26% decrease in overall cancer incidence excluding prostate cyclosporine and tacrolimus are associated with an increased carcinoma (hazard ratio 0.74). The authors postulate that the risk of malignancy . In a French prospective randomized increase in prostate cancer diagnosis is due to sirolimus, effects study involving 231 renal allograft recipients, low-dose (75– on screen detection. In addition, two meta-analyses have been 125 ng/mL) cyclosporine was associated with a lower incidence Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/315/4568992 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Risk factors for post-transplant malignancies | 321 Table 3. Recommendations for waiting times after cancer [203–206] published demonstrating a lower overall cancer incidence with the use of sirolimus [133, 194]. In the meta-analysis of Knoll Decisions regarding waiting time should be individualized and it et al. , including 21 randomized controlled trials with should be expalined to all patients with a history of cancer that patient-level data from 5876 patients, it was demonstrated that they are at increased risk of de novo malignancy post-transplanta- sirolimus was associated with a 40% reduction in malignancy tion. Recommended waiting periods before transplantation do not risk and a 56% reduction in the risk of non-melanoma skin cancer guarantee no recurrence of malignancy after transplantation (0.44, 0.30 to 0.63) compared with controls. This effect is restricted Absolute contraindication for transplantation to patients converting to sirolimus from another immunosup- Uncontrolled or untreated malignancies pressive regimen, as analysis of de novo sirolimus trials revealed Multiple myeloma no difference in malignancy risk between sirolimus and controls Advanced breast cancer (Stage III or IV) . Moreover, in a study analyzing Medicare claims data for • Colorectal cancer (Stage D) transplant recipients, de novo use of sirolimus was associated • Advanced prostate cancer (Grade 4 or 5, T3c, T4, Nþ,Mþ) with a 22% increased risk of PTLD . Remarkably, in the meta- No waiting time analysis of Knoll et al. , the decreased risk of cancer develop- Superﬁcial bladder cancer Non-metastatic, basal cell carcinoma ment was associated with an increased overall mortality risk due Prostatic cancer microscopic (focal, microscopic low-grade to cardiovascular and infection-related deaths. The authors spec- (Gleason’s grade 3), low risk) (T1a, T1c) disease ulate that increased sirolimus-induced cardiovascular risk factors Incidentally discovered T1 renal cell carcinoma (with no suspi- (anaemia, proteinuria, hyperglycaemia and hyperlipidemia) and cious histological features) overimmunosuppression with sirolimus might have contributed Monoclonal gammopathy of undetermined signiﬁcance to these findings . Based on these studies, universal siroli- 2-year waiting time mus use in kidney transplant recipients cannot be recommended Invasive bladder cancer at this time. In situ breast cancer Belatacept: For the co-stimulation blocker belatacept, an Localized cervical cancer inhibitor of T cell proliferation, PTLD risk appears similar to that Duke’s Stage A and B1 colorectal cancer seen under calcineurin inhibitor therapy , however, belata- Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, post-trans- cept is contraindicated in EBV-seronegative recipients. Although plant lymphoproliferative disorder, leukaemia initially a number of PTLDs of the central nervous system were In situ melanoma reported in patients treated with belatacept [197, 198], follow-up Lung cancer data of both the BENEFIT study and, more recently, a Phase 2 Prostatic cancer study where low immunologic risk patients were switched from Testicular cancer calcineurin inhibitor therapy to belatacept showed a mild albeit • Thyroid cancer small increase in post-transplant malignancies [199–202]. • Wilm’s tumour (a 1-year waiting period might be acceptable) 5-year waiting time Stage II breast cancer Screening • Extensive cervical cancer and non-in situ cancer of the uterus Colorectal cancer Stage C Since cancer before transplantation increases the risk of post- Melanoma transplant malignancy, guidelines have been developed outlining Large or invasive or symptomatic renal cell carcinoma waiting times for different types and stages of cancer (Table 3). A systematic review by Batabyal et al.  concluded that none of the available recommendations are backed by strong evidence. We recommend seeking an expert oncologist’s opinion regarding population. In a population-based cohort of Ontario between cancer-free survival, patient life expectancies and optimal cancer 1997 and 2010, 77.5, 69.8 and 91.4% of eligible solid organ trans- surveillance. Clinicians have to realize that even longer waiting plant recipients were not up to date with colorectal, cervical and times do not eliminate the risk for cancer recurrence and cancer- breast cancer screening, respectively . Solid organ transplant related death . In a Swedish population-based cohort of solid recipients with fewer co-morbidities, assessment by a primary organ transplant recipients, the increased rate of death was care provider and continuity of care by a transplant specialist at a greatest for patients with waiting times of 5 years but persisted transplant centre were associated with higher rates of becoming with waiting times of >10 years among recipients with prior screen up to date in this study . aggressive cancer types (gastrointestinal, breast, kidney/ urothelial and hematologic malignancies) . The optimal cancer screening strategy to detect post- Treatment of post-transplant cancer transplant cancers in an early stage is not defined (Table 4). In general, many experts recommend using general practice guide- In general, a reduction in immunosuppression is recommended lines in kidney transplant recipients [208–215]. Several centres or kidney transplant recipients upon cancer diagnosis. In the routinely screen for native kidney cancer, as the risk for kidney above-mentioned study of Yanik et al. , it was noted that the cancer is greatly increased in both the dialysis and kidney trans- incidence of infection-related cancers was higher and the inci- plant populations [3, 4, 16–23, 216, 217]. In a medical decision dence of ESRD-related cancers was lower during kidney function analysis, screening for kidney cancer in all transplant recipients intervals (time on immunosuppression), suggesting that a reduc- would have a small benefit at relatively high cost . However, tion of immunosuppression affects different cancer types differ- directed screening using ultrasound in those with documented ently. Similar findings were reported by van Leeuwen et al. , acquired cystic kidney disease or those with a previous cancer in who performed a population-based retrospective cohort study a contralateral kidney might be cost effective. Modelling studies and compared the cancer incidence in kidney transplant recipi- by Wong et al. [219, 220] suggest that screening for colon and cer- ents during periods of transplant function (and immunosuppres- vical cancer would be cost effective in the kidney transplant sion) and after transplant failure (when immunosuppression is Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/315/4568992 by Ed 'DeepDyve' Gillespie user on 20 June 2018 322 | B. Sprangers et al. ceased or reduced) . The SIRs for NHL, lip cancer and mela- noma were significantly elevated during periods of transplant function. For leukaemia and lung carcinoma, SIRs remained ele- vated after transplant failure, while the SIRs for kidney/urinary tract and thyroid cancers significantly increased after transplant failure. These data suggest that while the effect of immunosup- pression on cancer risk is rapidly reversible for some cancers (mainly infectious-related cancers), this does not hold true for other cancer types (ESRD-related cancers) . Some centres convert patients with non-melanoma skin cancer to mTOR ther- apy, as randomized clinical trials have shown fewer skin cancers in mTOR-treated patients [184, 185]. Also, for other solid and hematologic cancers, mTOR inhibitors have had marginal success [223, 224]. However, routine conversion to mTOR inhibi- tors to improve outcomes in all cancers or to prevent long-term cancer development in all solid organ transplant recipients is not widely practiced at this time, as data are lacking to support this practice. Outcome Data suggest that cancer as a cause of death is on the rise. For example, in Australia and New Zealand, cardiovascular deaths are decreasing while cancer mortality is increasing . Malignancy accounts for 8–10% of all deaths in the USA (2.6 deaths/1000 patient-years) and >30% of deaths in Australia (5/ 1000 patient-years) [1, 2]. The data regarding standardized mor- tality rates (SMRs) have been conflicting. While some studies have suggested that the cancer-related SMR has increased with the same magnitude as the SIR in transplant recipients , other studies have shown a more nuanced picture . In a study from Hong Kong, the cancer SIR and SMR in kidney transplant recipients were very similar (2.9 and 2.3, respectively) ; high SMRs were associated with lymphoma, leukaemia, kidney, colon, lung, bladder, melanoma and stomach cancers, while lymphoma, liver, colorectal and lung were associated with excess absolute risk of >25 deaths/100 000 patient-years . In a US registry analysis by Kiberd et al. , no overall excess mortality was observed in kidney transplant recipients. Cancer SMRs varied substantially with age group; cancer SMRs were 23-fold and 4.4-fold higher in patients <20 years and 20– 39 years of age, respectively, while cancer SMRs were lower in patients >60 years of age . The cancer death rates were >500/ 100 000 patient-years for patients >60 years of age compared with 13/100 000 patient-years for patients 20–39 years of age . So in older patients who are at the highest risk to die from can- cer, there is no increased risk to die from cancer in kidney trans- plant recipients. More specific data are available concerning post-transplant lymphoma. The 1-year survival in cadaveric kidney transplant recipients developing lymphoma was 60% and showed little improvement over the study period, while the 5-year survival was 40% . Interestingly, in this analysis the time of lymphoma development after transplantation did not influence survival: 5-year survival in kidney transplantation with lymphoma development <90 days post-transplant and >365 days post-transplant was 41.4% and 37.0%, respectively . Post-transplant lymphoma with lymph node involvement had a good prognosis while disseminated disease had a poor prognosis . Conclusion Malignancy is one of the most common causes of death in kid- ney transplant recipients. In general, the cancer incidence in Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/315/4568992 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Table 4. Recommendations for post-transplant cancer screening Guideline Skin cancer Cervical cancer Breast cancer Colorectal cancer Prostate cancer Liver Lymphoma Others AST kidney 2000  Self-screening Annually Every 1–2 years As in general Annually PSA Every 6–12 months Clinically every Annually prostate, Annually including PAP population and DRE AFP and US 3 months in ﬁrst year lung and bladder EBPG 2002  – Annually Recommended Recommended Annually PSA – – Annually prostate including PAP and DRE and kidney KDIGO 2009  Self-screening As in general As in general As in general – Annual AFP and US – – Annually population population population NKF 2009  Annually – – – – – – CST and CSN 2010  Self-screening Annually PAP As in general As in general – Annual AFP and US – – Annually population population RA 2011  Self-screening As in general As in general As in general –– – – Annually population population population KHA-CARI 2012  Self-screening Annually – – – – – – Annually DRE, digital rectal examination; AFP, Alpha fetoprotein; US, Ultra sound examination; PAP, PAP-mean Risk factors for post-transplant malignancies | 323 12. Pedotti P, Cardillo M, Rossini G et al. Incidence of cancer solid organ transplant recipients is increased 2- to 3-fold com- pared with the general population [3, 4]. Moreover, cancer- after kidney transplant: results from the North Italy trans- related mortality rates are also higher in solid organ transplant plant program. Transplantation 2003; 76: 1448–1451 recipients compared with the general population . Several 13. Marks WH, Ilsley JN, Dharnidharka VR. Posttransplantation risk factors for post-transplantation cancer development have lymphoproliferative disorder in kidney and heart transplant been identified and immunosuppression is considered the most recipients receiving thymoglobulin: a systematic review. Transplant Proc 2011; 43: 1395–1404 important risk factor, as it decreases the immunologic control of oncogenic viral infection and immunosurveillance. Currently 14. Cherikh WS, Kauffman HM, McBride MA et al. Association available immunosuppressive agents influence different anti- of the type of induction immunosuppression with post- cancer pathways and mTOR inhibitors seem to have a transplant lymphoproliferative disorder, graft survival, and patient survival after primary kidney transplantation. favourable profile in this respect. However, the increased mor- tality associated with mTOR inhibitor use in a recent meta- Transplantation 2003; 76: 1289–1293 analysis argues against their universal use in renal allograft 15. Quinlan SC, Pfeiffer RM, Morton LM et al. Risk factors for recipients or switching to mTOR inhibition in all patients with early-onset and late-onset post-transplant lymphoprolifer- ative disorder in kidney recipients in the United States. Am post-transplant malignancies. Intense collaboration between nephrologists and oncologists is needed in this field to design J Hematol 2011; 86: 206–209 16. Collett D, Mumford L, Banner NR et al. Comparison of the safer immunosuppressive regimens and define optimal screen- ing and treatment strategies in kidney transplant recipients. incidence of malignancy in recipients of different types of organ: a UK Registry audit. Am J Transplant 2010; 10: 1889–1896 17. Villeneuve PJ, Schaubel DE, Fenton SS et al. Cancer inci- Funding dence among Canadian kidney transplant recipients. Am J Transplant 2007; 7: 941–948 No funding was involved in the preparation of this 18. Webster AC, Craig JC, Simpson JM et al. Identifying high risk Manuscript. groups and quantifying absolute risk of cancer after kidney transplantation: a cohort study of 15,183 recipients. Am J References Transplant 2007; 7: 2140–2151 19. Adami J, Gabel H, Lindelof B et al. Cancer risk following 1. Pilmore H, Dent H, Chang S et al. Reduction in cardiovascu- organ transplantation: a nationwide cohort study in lar death after kidney transplantation. Transplantation 2010; Sweden. Br J Cancer 2003; 89: 1221–1227 89: 851–857 20. Maisonneuve P, Agodoa L, Gellert R et al. Cancer in patients 2. Collins AJ, Foley RN, Chavers B et al. United States Renal on dialysis for end-stage renal disease: an international Data System 2011 annual data report: atlas of chronic kid- collaborative study. Lancet 1999; 354: 93–99 ney disease & end-stage renal disease in the United States. 21. Kyllonen L, Salmela K, Pukkala E. Cancer incidence in a Am J Kidney Dis 2012; 59: e1–e420 kidney-transplanted population. Transpl Int 2000; 13: 3. Engels EA, Pfeiffer RM, Fraumeni JF Jr et al. Spectrum of can- S394–S398 cer risk among US solid organ transplant recipients. JAMA 22. Li WH, Chen YJ, Tseng WC et al. Malignancies after renal 2011; 306: 1891–1901 transplantation in Taiwan: a nationwide population-based 4. Grulich AE, van Leeuwen MT, Falster MO et al. Incidence of study. Nephrol Dial Transplant 2012; 27: 833–839 cancers in people with HIV/AIDS compared with immuno- 23. Kasiske BL, Snyder JJ, Gilbertson DT et al. Cancer after kid- suppressed transplant recipients: a meta-analysis. Lancet ney transplantation in the United States. Am J Transplant 2007; 370: 59–67 2004; 4: 905–913 5. Kiberd BA, Rose C, Gill JS. Cancer mortality in kidney trans- 24. Vajdic CM, van Leeuwen MT, McDonald SP et al. Increased plantation. Am J Transplant 2009; 9: 1868–1875 incidence of squamous cell carcinoma of eye after kidney 6. Stallone G, Infante B, Grandaliano G. Management and pre- transplantation. J Natl Cancer Inst 2007; 99: 1340–1342 vention of post-transplant malignancies in kidney trans- 25. Stewart JH, Vajdic CM, van Leeuwen MT et al. The pattern of plant recipients. Clin Kidney J 2015; 8: 637–644 excess cancer in dialysis and transplantation. Nephrol Dial 7. Caillard S, Dharnidharka V, Agodoa L et al. Posttransplant Transplant 2009; 24: 3225–3231 lymphoproliferative disorders after renal transplantation 26. Yanik EL, Nogueira LM, Koch L et al. Comparison of cancer in the United States in era of modern immunosuppression. diagnoses between the US solid organ transplant registry Transplantation 2005; 80: 1233–1243 and linked central cancer registries. Am J Transplant 2016; 8. Hibberd AD, Trevillian PR, Wlodarzcyk JH et al. Cancer risk 16: 2986–2993 associated with ATG/OKT3 in renal transplantation. 27. Lanza LL, Wang L, Simon TA et al. Epidemiologic critique of Transplant Proc 1999; 31: 1271–1272 literature on post-transplant neoplasms in solid organ 9. van Leeuwen MT, Grulich AE, Webster AC et al. transplantation. Clin Transplant 2009; 23: 582–588 Immunosuppression and other risk factors for early and 28. Stewart T, Tsai SC, Grayson H et al. Incidence of de-novo late non-Hodgkin lymphoma after kidney transplantation. breast cancer in women chronically immunosuppressed Blood 2009; 114: 630–637 after organ transplantation. Lancet 1995; 346: 796–798 10. Bustami RT, Ojo AO, Wolfe RA et al. Immunosuppression and 29. Lim WH, Turner RM, Chapman JR, Ma MK et al. Acute rejec- the risk of post-transplant malignancy among cadaveric ﬁrst tion, T-cell-depleting antibodies, and cancer after trans- kidney transplant recipients. Am J Transplant 2004; 4: 87–93 plantation. Transplantation 2014; 97: 817–825 11. Kirk AD, Cherikh WS, Ring M et al. Dissociation of deple- 30. Opelz G, Dohler B. Lymphomas after solid organ transplan- tional induction and posttransplant lymphoproliferative tation: a collaborative transplant study report. Am J disease in kidney recipients treated with alemtuzumab. Transplant 2004; 4: 222–230 Am J Transplant 2007; 7: 2619–2625 Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/315/4568992 by Ed 'DeepDyve' Gillespie user on 20 June 2018 324 | B. Sprangers et al. 52. Kauffman HM, McBride MA, Delmonico FL. First report of 31. Kotton CN, Huprikar S, Kumar D. Transplant infectious dis- eases: a review of the scientiﬁc registry of transplant recipi- the United Network for Organ Sharing Transplant Tumour ents published data. Am J Transplant 2017; 17: 1439–1446 Registry: donors with a history of cancer. Transplantation 32. Saeian K, Franco J, Komorowski RA et al. Hepatocellular 2000; 70: 1747–1751 carcinoma after renal transplantation in the absence of cir- 53. Ma MK, Lim WH, Turner RM et al. The risk of cancer in recip- rhosis or viral hepatitis: a case series. Liver Transpl Surg ients of living-donor, standard and expanded criteria 1999; 5: 46–49 deceased donor kidney transplants: a registry analysis. 33. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ Transplantation 2014; 98: 1286–1293 transplantation. N Engl J Med 2003; 348: 1681–1691 54. Francis A, Johnson DW, Craig JC et al. Incidence and predic- 34. Penn I. De novo malignances in pediatric organ transplant tors of cancer following kidney transplantation in child- recipients. Pediatr Transplant 1998; 2: 56–63 hood. Am J Transplant 2017; 17: 2650–2658 35. Karami S, Yanik EL, Moore LE et al. Risk of renal cell carci- 55. Farrugia D, Mahboob S, Cheshire J et al. Malignancy-related noma among kidney transplant recipients in the United mortality following kidney transplantation is common. States. Am J Transplant 2016; 16: 3479–3489 Kidney Int 2014; 85: 1395–1403 56. Yanik EL, Clarke CA, Snyder JJ. Variation in cancer incidence 36. Stewart JH, Buccianti G, Agodoa L et al. Cancers of the kid- ney and urinary tract in patients on dialysis for end-stage among patients with ESRD during kidney function and non- renal disease: analysis of data from the United States, function intervals. J Am Soc Nephrol 2016; 27: 1495–1504 Europe, and Australia and New Zealand. J Am Soc Nephrol 57. Brattstrom C, Granath F, Edgren G et al. Overall and cause- 2003; 14: 197–207 speciﬁc mortality in transplant recipients with a pretrans- 37. Riella LV. Malignancy after kidney transplantation. Kidney plantation cancer history. Transplantation 2013; 96: 297–305 Transplant eBook 2015, version 1.3, pp. 172–178 58. Acuna SA, Huang JW, Daly C et al. Outcomes of solid organ 38. Wong G, Turner RM, Chapman JR et al. Time on dialysis and transplant recipients with preexisting malignancies in cancer risk after kidney transplantation. Transplantation remission: a systematic review and meta-analysis. 2013; 95: 114–121 Transplantation 2017; 101: 471–481 39. Webster AC, Ruster LP, McGee R et al. Interleukin 2 receptor 59. Hiesse C, Rieu P, Kriaa F et al. Malignancy after renal trans- antagonists for kidney transplant recipients. Cochrane plantation: analysis of incidence and risk factors in 1700 Database Syst Rev 2010; 1: 1–146 patients followed during a 25-year period. Transplant Proc 40. Penn I. Malignant melanoma in organ allograft recipients. 1997; 29: 831–833 Transplantation 1996; 61: 274–278 60. Muruve NA, Shoskes DA. Genitourinary malignancies in 41. Myron KH, McBride MA, Cherikh WS et al. Transplant tumour solid organ transplant recipients. Transplantation 2005; 80: registry: donor related malignancies. Transplantation 2002; 709–716 74: 358–362 61. Doublet JD, Peraldi MN, Gattegno B et al. Renal cell carci- 42. Birkeland SA, Storm HH. Risk for tumour and other disease noma of native kidneys: prospective study of 129 renal transmission by transplantation: a population-based study transplant patients. J Urol 1997; 158: 42–44 of unrecognized malignancies and other diseases in organ 62. Denton MD, Magee CC, Ovuworie C et al. Prevalence of renal donors. Transplantation 2002; 74: 1409–1413 cell carcinoma in patients with ESRD pre-transplantation: a 43. Pedotti P, Poli F, Longhi E et al. Epidemiologic study on the pathologic analysis. Kidney Int 2002; 61: 2201–2209 origin of cancer after kidney transplantation. Transplantation 63. Cornelis F, Buy X, Andre M et al. De novo renal tumours aris- 2004; 77: 426–428 ing in kidney transplants: midterm outcome after percuta- 44. Armanios MY, Grossman SA, Yang SC et al. Transmission of neous thermal ablation. Radiology 2011; 260: 900–907 glioblastoma multiforme following bilateral lung trans- 64. Yarosh DB. DNA repair, immunosuppression, and skin can- plantation from an affected donor: case study and review cer. Cutis 2004; 74: 10–13 of the literature. Neuro-Oncology 2004; 6: 259–263 65. Kricker A, Armstrong BK, English DR. Sun exposure and 45. Penn I. Donor transmitted disease: cancer. Transplant Proc non-melanocytic skin cancer. Cancer Causes Control 1994; 5: 1991; 23: 2629–2631 367–392 46. Buell JF, Trofe J, Hanaway MJ et al. Transmission of donor 66. Armstrong BK, Kricker A. The epidemiology of UV-induced cancer into cardiothoracic transplant recipients. Surgery skin cancer. J Photochem Photobiol B 2001; 63: 8–18 2001; 130: 660–666 67. Thompson SC, Jolley D, Marks R. Reduction of solar kerato- 47. Nalesnik MA, Woodle ES, Dimaio JM et al. Donor-transmit- ses by regular sunscreen use. N Engl J Med 1993; 329: ted malignancies in organ transplantation: assessment of 1147–1151 clinical risk. Am J Transplant 2011; 11: 1140–1147 68. Green A, Williams G, Neale R et al. Daily sunscreen applica- 48. Feng S, Buell JF, Cherikh WS et al. Organ donors with posi- tion and betacarotene supplementation in prevention of tive viral serology or malignancy: risk of disease transmis- basal-cell and squamous-cell carcinomas of the skin: a sion by transplantation. Transplantation 2002; 74: randomised controlled trial. Lancet 1999; 354: 723–729 1657–1663 69. Green AC, Williams GM, Logan V et al. Reduced melanoma 49. Kauffman HM. The United Network for Organ Sharing posi- after regular sunscreen use: randomized trial follow-up. tion on using donors with primary central nervous system J Clin Oncol 2011; 29: 257–263 malignancies. Transplantation 2005; 79: 622–623 70. Chen AC, Martin AJ, Choy B et al. A phase 3 randomized trial 50. Xiao D, Craig JC, Chapman JR et al. Donor cancer transmis- of nicotinamide for skin-cancer chemoprevention. N Engl J sion in kidney transplantation: a systematic review. Am J Med 2015; 373: 1618–1626 Transplant 2013; 13: 2645–2652 71. Sodhi A, Chaisuparat R, Hu J et al. The TSC2/mTOR pathway 51. Desai R, Collett D, Watson CJ et al. Cancer transmission from drives endothelial cell transformation induced by the organ donors-unavoidable but low risk. Transplantation 2012; Kaposi’s sarcoma-associated herpesvirus G protein- 94: 1200–1207 coupled receptor. Cancer Cell 2006; 10: 133–143 Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/315/4568992 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Risk factors for post-transplant malignancies | 325 89. Courivaud C, Bamoulid J, Gaugler B et al. Cytomegalovirus 72. Montaner S, Sodhi A, Ramsdell AK et al. The Kaposi’s sarcoma-associated herpesvirus G protein-coupled recep- exposure, immune exhaustion and cancer occurrence in tor as a therapeutic target for the treatment of Kaposi’s sar- renal transplant recipients. Transpl Int 2012; 25: 948–955 coma. Cancer Res 2006; 66: 168–174 90. Desai R, Collett D, Watson CJ et al. Impact of cytomegalovi- 73. Hosseini-Moghaddam SM, Soleimanirahbar A, Mazzulli T rus on long-term mortality and cancer risk after organ et al. Post renal transplantation Kaposi’s sarcoma: a review transplantation. Transplantation 2015; 99: 1989–1994 of its epidemiology, pathogenesis, diagnosis, clinical 91. Wong G, Chakera A, Chapman JR et al. Cytomegalovirus aspects, and therapy. Transpl Infect Dis 2012; 14: 338–345 and cancer after kidney transplantation: Role of the human 74. Young LS, Rickinson AB. Epstein-Barr virus: 40 years on. Nat leukocyte antigen system? Transpl Infect Dis 2017; 19: 10 Rev Cancer 2004; 4: 757–768 92. Verghese PS, Schmeling DO, Knight JA. Valganciclovir 75. Grywalska E, Rolinski J. Epstein-Barr virus-associated lym- administration to kidney donors to reduce the burden of phomas. Semin Oncol 2015; 42: 291–303 cytomegalovirus and Epstein-Barr virus transmission dur- 76. Walker RC, Paya CV, Marshall WF et al. Pretransplantation ing transplantation. Transplantation 2015; 99: 1186–1191 seronegative Epstein-Barr virus status is the primary risk 93. Halloran PF. Immunosuppressive drugs for kidney trans- factor for posttransplantation lymphoproliferative disorder plantation. N Engl J Med 2004; 351: 2715–2729 in adult heart, lung, and other solid organ transplantations. 94. Borsig L, Wolf MJ, Roblek M et al. Inﬂammatory chemokines J Heart Lung Transplant 1995; 14: 214–221 and metastasis–tracing the accessory. Oncogene 2014; 33: 77. Sampaio MS, Cho YW, Shah T et al. Impact of Epstein-Barr 3217–3224 virus donor and recipient serostatus on the incidence of 95. Eiro N, Vizoso FJ. Inﬂammation and cancer. World J post-transplant lymphoproliferative disorder in kidney Gastrointest Surg 2012; 4: 62–72 transplant recipients. Nephrol Dial Transplant 2012; 27: 96. Opelz G, Henderson R. Incidence of non-Hodgkin lym- 2971–2979 phoma in kidney and heart transplant recipients. Lancet 78. Dharnidharka VR, Lamb KE, Gregg JA et al. Associations 1993; 342: 1514–1516 between EBV serostatus and organ transplant type in PTLD 97. Kremers WK, Devarbhavi HC, Wiesner RH et al. Post-trans- risk: an analysis of the SRTR National Registry Data in the plant lymphoproliferative disorders following liver trans- United States. Am J Transplant 2012; 12: 976–983 plantation: incidence, risk factors and survival. Am J 79. Kenan DJ, Mieczkowski PA, Burger-Calderon R et al. The Transplant 2006; 6: 1017–1024 oncogenic potential of BK-polyomavirus is linked to viral 98. Hojo M, Morimoto T, Maluccio M et al. Cyclosporine induces integration into the human genome. J Pathol 2015; 237: cancer progression by a cell-autonomous mechanism. 379–389 Nature 1999; 397: 530–534 80. Kenan DJ, Mieczkowski PA, Latulippe E. Polyomavirus 99. Herman M, Weinstein T, Korzets A et al. Effect of cyclo- genomic integration and large T antigen expression: evolv- sporin A on DNA repair and cancer incidence in kidney ing paradigms in human oncogenesis. Am J Transplant 2017; transplant recipients. J Lab Clin Med 2001; 137: 14–20 17: 1674–1680 100. Shihab FS, Bennett WM, Isaac J. Nitric oxide modulates vas- 81. Liu S, Chaudhry MR, Berrebi AA et al. Polyomavirus replica- cular endothelial growth factor and receptors in chronic tion and smoking are independent risk factors for bladder cyclosporine nephrotoxicity. Kidney Int 2003; 63: 522–533 cancer after renal transplantation. Transplantation 2017; 101. Guba M, Graeb C, Jauch KW. Pro- and anti-cancer effects of 101: 1488–1494 immunosuppressive agents used in organ transplantation. 82. Papadimitriou JC, Randhawa P, Rinaldo CH et al. BK polyo- Transplantation 2004; 77: 1777–1782 mavirus infection and renourinary tumorigenesis. Am J 102. Morisaki T, Matsunaga H, Beppu K et al. A combination of Transplant 2016; 16: 398–406 cyclosporin-A (CsA) and interferon-gamma (INF-gamma) 83. Oikawa M, Hatakeyama S, Fujita T et al. BK virus-associated induces apoptosis in human gastric carcinoma cells. urothelial carcinoma of a ureter graft in a renal transplant Anticancer Res 2000; 20: 3363–3373 recipient: a case report. Transplant Proc 2014; 46: 616–619 103. Nomura T, Yamamoto H, Mimata H et al. Enhancement by 84. Yan L, Salama ME, Lanciault C et al. Polyomavirus large T cyclosporin A of taxol-induced apoptosis of human urinary antigen is prevalent in urothelial carcinoma post-kidney bladder cancer cells. Urol Res 2002; 30: 102–111 transplant. Hum Pathol 2016; 48: 122–131 104. Mistrikova J, Mrmusova M, Durmanova V et al. Increased 85. Nickeleit V, Singh HK, Goldsmith CS et al. BK virus- neoplasm development due to immunosuppressive treat- associated urinary bladder carcinoma in transplant recipi- ment with FK-506 in BALB/C mice persistently infected ents: productive or nonproductive polyomavirus infections with the mouse herpesvirus (MHV-72). Viral Immunol 1999; in tumor cells? Hum Pathol 2013; 44: 2870–2871 12: 237–247 86. Kausman JY, Somers GR, Francis DM et al. Association of 105. Swann PF, Waters TR, Moulton DC et al. Role of postreplica- renal adenocarcinoma and BK virus nephropathy post tive DNA mismatch repair in the cytotoxic action of thio- transplantation. Pediatr Nephrol 2004; 19: 459–462 guanine. Science 1996; 273: 1109–1111 87. Emerson LL, Carney HM, Layﬁeld LJ et al. Collecting duct 106. Offman J, Opelz G, Doehler B et al. Defective DNA mismatch carcinoma arising in association with BK nephropathy repair in acute myeloid leukemia/myelodysplastic syn- post-transplantation in a pediatric patient. A case report drome after organ transplantation. Blood 2004; 104: 822–828 with immunohistochemical and in situ hybridization 107. Buell JF, Gross TG, Woodle ES. Malignancy after transplan- study. Pediatr Transplant 2008; 12: 600–605 tation. Transplantation 2005; 80: S254–S264 88. Couzi L, Levaillant Y, Jamai A et al. Cytomegalovirus- 108. Nagai M, Natsumeda Y, Konno Y et al. Selective up- induced cd T cells associate with reduced cancer risk regulation of type II inosine 5 -monophosphate dehydro- after kidney transplantation. JAmSoc Nephrol 2010; 21: genase messenger RNA expression in human leukemias. 181–188 Cancer Res 1991; 51: 3886–3890 Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/315/4568992 by Ed 'DeepDyve' Gillespie user on 20 June 2018 326 | B. Sprangers et al. induction via signaling to initial events. Ann N Y Acad Sci 109. Engl T, Makarevic J, Relja B et al. Mycophenolate mofetil modulates adhesion receptors of the beta1 integrin family 2002; 973: 31–43 on tumor cells: impact on tumor recurrence and malig- 128. Hibberd AD, Trevillian PR, Wlodarczyk JH et al. Effect of immu- nancy. BMC Cancer 2005; 5: 4 nosuppression for primary renal disease on the risk of cancer 110. Weber G, Hager JC, Lui MS et al. Biochemical programs of in subsequent renal transplantation: a population-based ret- slowly and rapidly growing human colon carcinoma xeno- rospective cohort study. Transplantation 2013; 95: 122–127 grafts. Cancer Res 1981; 41: 854–859 129. Marcen R. Immunosuppressive drugs in kidney transplan- 111. Jackson RC, Weber G, Morris HP. IMP dehydrogenase, an tation: impact on patient survival, and incidence of cardio- enzyme linked with proliferation and malignancy. Nature vascular disease, malignancy and infection. Drugs 2009; 69: 1975; 256: 331–333 2227–2243 112. Yu J, Lemas V, Page T et al. Induction of erythroid differen- 130. Gallagher MP, Kelly PJ, Jardine M et al. Long-term cancer tiation in K562 cells by inhibitors of inosine monophos- risk of immunosuppressive regimens after kidney trans- phate dehydrogenase. Cancer Res 1989; 49: 5555–5560 plantation. J Am Soc Nephrol 2010; 21: 852–858 113. Ohsugi Y, Suzuki S, Takagaki Y. Antitumor and immuno- 131. Knight SR, Russell NK, Barcena L et al. Mycophenolate suppressive effects of mycophenolic acid derivatives. mofetil decreases acute rejection and may improve graft Cancer Res 1976; 36: 2923–2927 survival in renal transplant recipients when compared 114. Carter SB, Franklin TJ, Jones DF et al. Mycophenolic acid: an with azathioprine: a systematic review. Transplantation anti-cancer compound with unusual properties. Nature 2009; 87: 785–794 1969; 223: 848–850 132. Kauffman HM, Cherikh WS, Cheng Y. Maintenance immu- 115. Heemann U, Azuma H, Hamar P et al. Mycophenolate mofe- nosuppression with target-of-rapamycin inhibitors is asso- til inhibits lymphocyte binding and the upregulation of ciated with a reduced incidence of de novo malignancies. adhesion molecules in acute rejection of rat kidney allog- Transplantation 2005; 80: 883–889 rafts. Transpl Immunol 1996; 4: 64–67 133. Knoll GA, Kokolo MB, Mallick R et al. Effect of sirolimus on 116. Leckel K, Beecken WD, Jonas D et al. The immunosuppres- malignancy and survival after kidney transplantation: sys- sive drug mycophenolate mofetil impairs the adhesion tematic review and meta-analysis of individual patient capacity of gastrointestinal tumour cells. Clin Exp Immunol data. BMJ 2014; 349: g6679 2003; 134: 238–245 134. Kauffman HM, Cherikh WS, McBride MA. Post-transplant 117. Vignot S, Faivre S, Aguirre D et al. mTOR-targeted therapy of de novo malignancies in renal transplant recipients: the cancer with rapamycin derivatives. Ann Oncol 2005; 16: past and present. Transpl Int 2006; 19: 607–620 525–537 135. Sampaio MS, Cho YW, Qazi Y et al. Posttransplant malig- 118. Muthukkumar S, Ramesh TM, Bondada S. Rapamycin, a nancies in solid organ adult recipients: an analysis of the potent immunosuppressive drug, causes programmed cell U.S. National Transplant Database. Transplantation 2012; 94: death in B lymphoma cells. Transplantation 1995; 60: 990–998 264–270 136. Sant AJ, McMichael A. Revealing the role of CD4 T cells in 119. Luan FL, Ding R, Sharma VK et al. Rapamycin is an effective viral immunity. J Exp Med 2012; 209: 1391–1395 inhibitor of human renal cancer metastasis. Kidney Int 2003; 137. Lakshmi NB, Eshvendar RK, Shantikumar S et al. Immune 63: 917–926 system: a double-edged sword in cancer. Inﬂamm Res 2013; 120. Nepomuceno RR, Balatoni CE, Natkunam Y et al. 62: 823–834 Rapamycin inhibits the interleukin 10 signal transduction 138. Zand MS. B-cell activity of polyclonal antithymocyte globu- pathway and the growth of Epstein Barr virus B-cell lym- lins. Transplantation 2006; 82: 1387–1395 phomas. Cancer Res 2003; 63: 4472–4480 139. Hardinger KL. Rabbit antithymocyte globulin induction 121. Garcia-Morales P, Hernando E, Carrasco-Garcia E et al. therapy in adult renal transplantation. Pharmacotherapy Cyclin D3 is down-regulated by rapamycin in HER-2- 2006; 26: 1771–1783 overexpressing breast cancer cells. Mol Cancer Ther 2006; 5: 140. Midtvedt K, Fauchald P, Lien B et al. Individualized T cell 2172–2181 monitored administration of ATG versus OKT3 in steroid- 122. Guba M, von BP, Steinbauer M et al. Rapamycin inhibits pri- resistant kidney graft rejection. Clin Transplant 2003; 17: mary and metastatic tumor growth by antiangiogenesis: 69–74 involvement of vascular endothelial growth factor. Nat Med 141. Opelz G, Naujokat C, Daniel V et al. Disassociation between 2002; 8: 128–135 risk of graft loss and risk of non-Hodgkin lymphoma with 123. Huber S, Bruns CJ, Schmid G et al. Inhibition of the mamma- induction agents in renal transplant recipients. lian target of rapamycin impedes lymphangiogenesis. Transplantation 2006; 81: 1227–1233 Kidney Int 2007; 71: 771–777 142. Hall EC, Engels EA, Pfeiffer RM et al. Association of antibody 124. Krams SM, Martinez OM. Epstein-Barr virus, rapamycin, induction immunosuppression with cancer after kidney and host immune responses. Curr Opin Organ Transplant transplantation. Transplantation 2015; 99: 1051–1057 2008; 13: 563–568 143. Swinnen LJ, Fisher RI. OKT3 monoclonal antibodies induce 125. Kawada J, Ito Y, Iwata S et al. mTOR inhibitors induce cell- interleukin-6 and interleukin-10: a possible cause of lym- cycle arrest and inhibit tumor growth in Epstein-Barr virus- phoproliferative disorders associated with transplantation. associated T and natural killer cell lymphoma cells. Clin Curr Opin Nephrol Hypertens 1993; 2: 670–678 Cancer Res 2014; 20: 5412–5422 144. Shapiro R, Young JB, Milford EL et al. Immunosuppression: 126. Adamson AL, Le BT, Siedenburg BD. Inhibition of mTORC1 evolution in practice and trends, 1993-2003. Am J Transplant inhibits lytic replication of Epstein-Barr virus in a cell-type 2005; 5: 874–886 speciﬁc manner. Virol J 2014; 11: 110–111 145. Meier-Kriesche HU, Li S et al. Immunosuppression: evolu- tion in practice and trends, 1994-2004. Am J Transplant 2006; 127. Brenneisen P, Sies H, Scharffetter-Kochanek K. Ultraviolet- B irradiation and matrix metalloproteinases: from 6: 1111–1131 Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/315/4568992 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Risk factors for post-transplant malignancies | 327 anti-il2 receptor monoclonal antibodies? Am J Transplant 146. Markmann JF, Fishman JA. Alemtuzumab in kidney- transplant recipients. N Engl J Med 2011; 364: 1968–1969 2017; 17: 22–27 147. Dharnidharka VR. Post-transplant lymphoproliferative dis- 164. Tanriover B, Zhang S, MacConmara M et al. Induction thera- ease: association with induction therapy? Drugs 2006; 66: pies in live donor kidney transplantation on tacrolimus and mycophenolate with or without steroid maintenance. 429–438 148. Dharnidharka VR, Tejani AH, Ho PL et al. Post-transplant Clin J Am Soc Nephrol 2015; 10: 1041–1049 lymphoproliferative disorder in the United States: young 165. Tanriover B, Jaikaransingh V, MacConmara MP et al. Acute Caucasian males are at highest risk. Am J Transplant 2002; 2: rejection rates and graft outcomes according to induction 993–998 regimen among recipients of kidneys from deceased 149. Dharnidharka VR, Sullivan EK, Stablein DM et al. Risk fac- donors treated with tacrolimus and mycophenolate. Clin J tors for posttransplant lymphoproliferative disorder (PTLD) Am Soc Nephrol 2016; 11: 1650–1661 in pediatric kidney transplantation: a report of the North 166. Koyawala N, Silber JH, Rosenbaum PR et al. Comparing out- American Pediatric Renal Transplant Cooperative Study comes between antibody induction therapies in kidney (NAPRTCS). Transplantation 2001; 71: 1065–1068 transplantation. J Am Soc Nephrol 2017; 28: 2188–2200 150. Mohty M, Bacigalupo A, Saliba F et al. New directions for 167. Ruiz P, Soares MF, Garcia M et al. Lymphoplasmacytic rabbit antithymocyte globulin (ThymoglobulinV) in solid hyperplasia (possibly pre-PTLD) has varied expression and organ transplants, stem cell transplants and autoimmun- appearance in intestinal transplant recipients receiving ity. Drugs 2014; 74: 1605–1634 Campath immunosuppression. Transplant Proc 2004; 36: 151. Dharnidharka VR, Stevens G. Risk for post-transplant lym- 386–387 phoproliferative disorder after polyclonal antibody induc- 168. Dantal J, Hourmant M, Cantarovich D et al. Effect of long- tion in kidney transplantation. Pediatr Transplant 2005; 9: term immunosuppression in kidney-graft recipients on 622–626 cancer incidence: randomised comparison of two cyclo- 152. Kasiske BL, Kukla A, Thomas D et al. Lymphoproliferative sporin regimens. Lancet 1998; 351: 623–628 disorders after adult kidney transplant: epidemiology and 169. Sampaio MS, Cho YW, Shah T et al. Association of immuno- comparison of registry report with claims-based diagnoses. suppressive maintenance regimens with posttransplant Am J Kidney Dis 2011; 58: 971–980 lymphoproliferative disorder in kidney transplant recipi- 153. Faull RJ, Hollett P, McDonald SP. Lymphoproliferative dis- ents. Transplantation 2012; 93: 73–81 ease after renal transplantation in Australia and New 170. Dayton JD, Richmond ME, Weintraub RG et al. Role of immu- Zealand. Transplantation 2005; 80: 193–197 nosuppression regimen in post-transplant lymphoprolifer- 154. Gajarski RJ, Blume ED, Urschel S et al. Infection and malig- ative disorder in pediatric heart transplant patients. J Heart nancy after pediatric heart transplantation: the role of Lung Transplant 2011; 30: 420–425 induction therapy. J Heart Lung Transplant 2011; 30: 299–308 171. Dharnidharka VR, Ho PL, Stablein DM et al. Mycophenolate, 155. Caillard S, Lamy FX, Quelen C et al. Epidemiology of post- tacrolimus and post-transplant lymphoproliferative disorder: transplant lymphoproliferative disorders in adult kidney a report of the North American Pediatric Renal Transplant and kidney pancreas recipients: report of the French regis- Cooperative Study. Pediatr Transplant 2002; 6: 396–399 try and analysis of subgroups of lymphomas. Am J 172. Taylor L, Hughes RA, McPherson K. The risk of cancer from Transplant 2012; 12: 682–693 azathioprine as a treatment for multiple sclerosis. Eur J 156. Brennan DC, Daller JA, Lake KD et al. Rabbit antithymocyte Neurol 2004; 11: 141 173. Beauparlant P, Papp K, Haraoui B. The incidence of cancer globulin versus basiliximab in renal transplantation. N Engl J Med 2006; 355: 1967–1977 associated with the treatment of rheumatoid arthritis. 157. Brennan DC, Flavin K, Lowell JA et al. A randomized, double- Semin Arthritis Rheum 1999; 29: 148–158 blinded comparison of Thymoglobulin versus ATGAM for 174. Robson R, Cecka JM, Opelz G et al. Prospective registry- induction immunosuppressive therapy in adult renal trans- based observational cohort study of the long-term risk plant recipients. Transplantation 1999; 67: 1011–1018 of malignancies in renal transplant patients treated 158. Mourad G, Rostaing L, Legendre C et al. Sequential protocols with mycophenolate mofetil. Am J Transplant 2005; 5: using basiliximab versus antithymocyte globulins in renal- 2954–2960 transplant patients receiving mycophenolate mofetil and 175. O’Neill JO, Edwards LB, Taylor DO. Mycophenolate mofetil steroids. Transplantation 2004; 78: 584–590 and risk of developing malignancy after orthotopic heart 159. Hardinger KL, Schnitzler MA, Miller B et al. Five-year follow transplantation: analysis of the transplant registry of the up of thymoglobulin versus ATGAM induction in adult International Society for Heart and Lung Transplantation. J renal transplantation. Transplantation 2004; 78: 136–141 Heart Lung Transplant 2006; 25: 1186–1191 160. Noel C, Abramowicz D, Durand D et al. Daclizumab versus 176. Birkeland SA, Hamilton-Dutoit S. Is posttransplant lym- phoproliferative disorder (PTLD) caused by any speciﬁc antithymocyte globulin in high-immunological-risk renal transplant recipients. JAmSoc Nephrol 2009; 20: immunosuppressive drug or by the transplantation per se? 1385–1392 Transplantation 2003; 76: 984–988 161. Hellemans R, Hazzan M, Durand D et al. Daclizumab versus 177. Campistol JM, Eris J, Oberbauer R et al. Sirolimus therapy rabbit antithymocyte globulin in high-risk renal trans- after early cyclosporine withdrawal reduces the risk for plants: ﬁve-year follow-up of a randomized study. Am J cancer in adult renal transplantation. J Am Soc Nephrol 2006; Transplant 2015; 15: 1923–1932 17: 581–589 162. Brennan DC, Schnitzler MA. Long-term results of rabbit 178. Luan FL, Hojo M, Maluccio M et al. Rapamycin blocks antithymocyte globulin and basiliximab induction. N Engl J tumour progression: unlinking immunosuppression from Med 2008; 359: 1736–1738 antitumor efﬁcacy. Transplantation 2002; 73: 1565–1572 163. Hellemans R, Bosmans JL, Abramowicz D. Induction ther- 179. Campistol JM, Gutierrez-Dalmau A, Torregrosa JV. apy for kidney transplant recipients: do we still need Conversion to sirolimus: a successful treatment for Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/315/4568992 by Ed 'DeepDyve' Gillespie user on 20 June 2018 328 | B. Sprangers et al. versus cyclosporine in renal transplant recipients (BENEFIT posttransplantation Kaposi’s sarcoma. Transplantation 2004; 77: 760–762 study). Am J Transplant 2010; 10: 535–546 180. Euvrard S, Ulrich C, Lefrancois N. Immunosuppressants 198. Durrbach A, Pestana JM, Pearson T et al. A phase III study of and skin cancer in transplant patients: focus on rapamycin. belatacept versus cyclosporine in kidney transplants from Dermatol Surg 2004; 30: 628–633 extended criteria donors (BENEFIT-EXT study). Am J 181. Kahan BD, Yakupoglu YK, Schoenberg L et al. Low incidence Transplant 2010; 10: 547–557 of malignancy among sirolimus/cyclosporine-treated renal 199. Vincenti F, Larsen CP, Alberu J et al. Three-year outcomes transplant recipients. Transplantation 2005; 80: 749–758 from BENEFIT, a randomized, active-controlled, parallel- 182. Stallone G, Schena A, Infante B et al. Sirolimus for Kaposi’s group study in adult kidney transplant recipients. Am J sarcoma in renal-transplant recipients. N Engl J Med 2005; Transplant 2012; 12: 210–217 352: 1317–1323 200. Rostaing L, Vincenti F, Grinyo J et al. Long-term belatacept 183. Lebbe C, Euvrard S, Barrou B et al. Sirolimus conversion for exposure maintains efﬁcacy and safety at 5 years: results patients with posttransplant Kaposi’s sarcoma. Am J from the long-term extension of the BENEFIT study. Am J Transplant 2006; 6: 2164–2168 Transplant 2013; 13: 2875–2883 201. Vincenti F, Rostaing L, Grinyo J et al. Belatacept and long- 184. Euvrard S, Morelon E, Rostaing L et al. Sirolimus and secon- dary skin-cancer prevention in kidney transplantation. N term outcomes in kidney transplantation. N Engl J Med Engl J Med 2012; 367: 329–339 2016; 374: 333–343 185. Campbell SB, Walker R, Tai SS et al. Randomized controlled 202. Grinyo JM, Del Carmen RM, Alberu J et al. Safety and efﬁcacy trial of sirolimus for renal transplant recipients at high risk outcomes 3 years after switching to belatacept from a calci- for nonmelanoma skin cancer. Am J Transplant 2012; 12: neurin inhibitor in kidney transplant recipients: results 1146–1156 from a phase 2 randomized trial. Am J Kidney Dis 2017; 69: 186. Kreis H, Oberbauer R, Campistol JM et al. Long-term beneﬁts 587–594 with sirolimus-based therapy after early cyclosporine with- 203. Penn I. The effect of immunosuppression on pre-existing drawal. J Am Soc Nephrol 2004; 15: 809–817 cancers. Transplantation 1993; 55: 742–747 187. Alberu J, Pascoe MD, Campistol JM et al. Lower malignancy 204. Kasiske BL, Cangro CB, Hariharan S et al. The evaluation of rates in renal allograft recipients converted to sirolimus- renal transplantation candidates: clinical practice guide- based, calcineurin inhibitor-free immunotherapy: 24- lines. Am J Transplant 2001; 1: 3–95 month results from the CONVERT trial. Transplantation 205. Knoll G, Cockﬁeld S, Blydt-Hansen T et al. Canadian Society 2011; 92: 303–310 of Transplantation: consensus guidelines on eligibility for 188. Ekberg H, Bernasconi C, Noldeke J et al. Cyclosporine, tacro- kidney transplantation. Can Med Assoc J 2005; 173: S1–25 limus and sirolimus retain their distinct toxicity proﬁles 206. Campbell S, Pilmore H, Gracey D et al. KHA-CARI guideline: despite low doses in the Symphony study. Nephrol Dial recipient assessment for transplantation. Nephrology 2013; Transplant 2010; 25: 2004–2010 18: 455–462 189. Flechner SM, Glyda M, Cockﬁeld S et al. The ORION study: 207. Batabyal P, Chapman JR, Wong G et al. Clinical practice comparison of two sirolimus-based regimens versus tacro- guidelines on wait-listing for kidney transplantation: con- limus and mycophenolate mofetil in renal allograft recipi- sistent and equitable? Transplantation 2012; 94: 703–713 ents. Am J Transplant 2011; 11: 1633–1644 208. Kasiske BL, Vazquez MA, Harmon WE et al. Recommendations 190. Budde K, Becker T, Arns W et al. Everolimus-based, for the outpatient surveillance of renal transplant recipients. calcineurin-inhibitor-free regimen in recipients of de-novo American Society of Transplantation. JAmSoc Nephrol 2000; kidney transplants: an open-label, randomised, controlled 11: S1–S86 trial. Lancet 2011; 377: 837–847 209. European best practice guidelines for renal transplantation. 191. Budde K, Lehner F, Sommerer C et al. Conversion from Section IV: long-term management of the transplant recipi- cyclosporine to everolimus at 4.5 months posttransplant: ent. Nephrol Dial Transplant 2002; 17: 1–67 3-year results from the randomized ZEUS study. Am J 210. KDIGO clinical practice guideline for the care of kidney trans- Transplant 2012; 12: 1528–1540 plant recipients. Am J Transplant 2009; 9(Suppl 3): S1–S155 192. Budde K, Lehner F, Sommerer C et al. Five-year outcomes in 211. Bia M, Adey DB, Bloom RD et al. KDOQI US commentary on kidney transplant patients converted from cyclosporine to the 2009 KDIGO clinical practice guideline for the care of kid- everolimus: the randomized ZEUS study. Am J Transplant ney transplant recipients. Am J Kidney Dis 2010; 56: 189–218 2015; 15: 119–128 212. Knoll GA, Blydt-Hansen TD, Campbell P et al. Canadian 193. Yanik EL, Gustafson SK, Kasiske BL et al. Sirolimus use and Society of Transplantation and Canadian Society of cancer incidence among US kidney transplant recipients. Nephrology commentary on the 2009 KDIGO clinical prac- Am J Transplant 2015; 15: 129–136 tice guideline for the care of kidney transplant recipients. 194. Yanik EL, Siddiqui K, Engels EA. Sirolimus effects on cancer Am J Kidney Dis 2010; 56: 219–246 incidence after kidney transplantation: a meta-analysis. 213. Baker R, Jardine A, Andrews P. Renal Association clinical Cancer Med 2015; 4: 1448–1459 practice guideline on post-operative care of the kidney 195. Nee R, Hurst FP, Dharnidharka VR et al. Racial variation in transplant recipient. Nephron Clin Pract 2011; 118: c311–c347 the development of posttransplant lymphoproliferative 214. Chadban SJ, Barraclough KA, Campbell SB et al. KHA-CARI disorders after renal transplantation. Transplantation 2011; guideline: KHA-CARI adaptation of the KDIGO clinical prac- 92: 190–195 tice guideline for the care of kidney transplant recipients. 196. Masson P, Henderson L, Chapman JR et al. Belatacept for Nephrology 2012; 17: 204–214 kidney transplant recipients. Cochrane Database Syst Rev 215. Acuna SA, Huang JW, Scott AL et al. Cancer screening rec- 2014; 11: 1–65 ommendations for solid organ transplant recipients: a sys- 197. Vincenti F, Charpentier B, Vanrenterghem Y et al. A phase III tematic review of clinical practice guidelines. Am J study of belatacept-based immunosuppression regimens Transplant 2017; 17: 103–114 Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/315/4568992 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Risk factors for post-transplant malignancies | 329 221. Acuna SA, Sutradhar R, Camacho X et al. Uptake of cancer 216. Schwarz A, Vatandaslar S, Merkel S et al. Renal cell carci- noma in transplant recipients with acquired cystic kidney screening tests among recipients of solid organ transplan- disease. Clin J Am Soc Nephrol 2007; 2: 750–756 tation. Am J Transplant 2017; 17: 2434–2443 217. Vajdic CM, McDonald SP, McCredie MR et al. Cancer inci- 222. van Leeuwen MT, Webster AC, McCredie MR et al. Effect of dence before and after kidney transplantation. JAMA 2006; reduced immunosuppression after kidney transplant fail- 296: 2823–2831 ure on risk of cancer: population based retrospective cohort 218. Wong G, Howard K, Webster AC et al. Screening for renal study. BMJ 2010; 340: c570 cancer in recipients of kidney transplants. Nephrol Dial 223. Khokhar NZ, Altman JK, Platanias LC. Emerging roles for Transplant 2011; 26: 1729–1739 mammalian target of rapamycin inhibitors in the treat- 219. Wong G, Howard K, Craig JC et al. Cost-effectiveness of col- ment of solid tumors and hematological malignancies. Curr orectal cancer screening in renal transplant recipients. Opin Oncol 2011; 23: 578–586 Transplantation 2008; 85: 532–541 224. Baldo P, Cecco S, Giacomin E et al. mTOR pathway and 220. Wong G, Howard K, Webster A et al. The health and eco- mTOR inhibitors as agents for cancer therapy. Curr Cancer nomic impact of cervical cancer screening and human pap- Drug Targets 2008; 8: 647–665 225. Cheung CY, Lam MF, Chu KH et al. Malignancies after kid- illomavirus vaccination in kidney transplant recipients. Transplantation 2009; 87: 1078–1091 ney transplantation: Hong Kong renal registry. Am J Transplant 2012; 12: 3039–3046 Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/315/4568992 by Ed 'DeepDyve' Gillespie user on 20 June 2018
Clinical Kidney Journal – Oxford University Press
Published: Oct 27, 2017
It’s your single place to instantly
discover and read the research
that matters to you.
Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.
All for just $49/month
Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly
Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.
Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.
Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.
All the latest content is available, no embargo periods.
“Hi guys, I cannot tell you how much I love this resource. Incredible. I really believe you've hit the nail on the head with this site in regards to solving the research-purchase issue.”Daniel C.
“Whoa! It’s like Spotify but for academic articles.”@Phil_Robichaud
“I must say, @deepdyve is a fabulous solution to the independent researcher's problem of #access to #information.”@deepthiw
“My last article couldn't be possible without the platform @deepdyve that makes journal papers cheaper.”@JoseServera