Identifying High Risk Groups and Quantifying Absolute Risk of Cancer After Kidney Transplantation: A Cohort Study of 15 183 Recipients

Transplant recipients have increased cancer risk, but data on risk variation across different patient groups are sparse. Rates and standardized rate ratios (SRR) of cancer (all sites, excluding nonmelanocytic skin and lip cancer) compared to the general population were calculated, using Australia and New Zealand Dialysis and Transplant Registry data. Within the transplant population, risk factors were identified (hazard ratios: HR; 95% CI) and absolute risk estimated for recipient groups. A total of 1642 (10.8%) of 15 183 recipients developed cancer. Risk was inversely related to age (SRR 15–30 children, 2 if >65 years). Females aged 25–29 had rates equivalent to women aged 55–59 from the general population. Age trend for lymphoma, colorectal and breast risk was similar; melanoma showed less variability across ages, prostate showed no risk increase. Within the transplanted population, risk was affected by age differently for each sex (p = 0.007), elevated by prior malignancy (HR 1.40; 1.03–1.89), white race (HR 1.36; 1.12–1.89), but reduced by diabetic end‐stage kidney disease (ESKD) (HR 0.67; 0.50–0.89). Cancer rates in kidney recipients are similar to nontransplanted people 20–30 years older, but absolute risk differs across patient groups. Men aged 45–54 surviving 10 years have cancer risks varying from 1 in 13 (non‐white, no prior cancer, diabetic ESKD) to 1 in 5 (white, prior cancer, other ESKD). Transplant recipients have increased cancer risk, but data on risk variation across different patient groups are sparse. Rates and standardized rate ratios (SRR) of cancer (all sites, excluding nonmelanocytic skin and lip cancer) compared to the general population were calculated, using Australia and New Zealand Dialysis and Transplant Registry data. Within the transplant population, risk factors were identified (hazard ratios: HR; 95% CI) and absolute risk estimated for recipient groups. A total of 1642 (10.8%) of 15 183 recipients developed cancer. Risk was inversely related to age (SRR 15–30 children, 2 if >65 years). Females aged 25–29 had rates equivalent to women aged 55–59 from the general population. Age trend for lymphoma, colorectal and breast risk was similar; melanoma showed less variability across ages, prostate showed no risk increase. Within the transplanted population, risk was affected by age differently for each sex (p = 0.007), elevated by prior malignancy (HR 1.40; 1.03–1.89), white race (HR 1.36; 1.12–1.89), but reduced by diabetic end‐stage kidney disease (ESKD) (HR 0.67; 0.50–0.89). Cancer rates in kidney recipients are similar to nontransplanted people 20–30 years older, but absolute risk differs across patient groups. Men aged 45–54 surviving 10 years have cancer risks varying from 1 in 13 (non‐white, no prior cancer, diabetic ESKD) to 1 in 5 (white, prior cancer, other ESKD). Kidney transplantation is the treatment of choice for most patients with end‐stage kidney disease (ESKD), as transplantation confers survival and quality of life advantages over dialysis (1Wolfe RA Ashby VB Milford EL et al.Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant.N Engl J Med. 1999; 341: 1725-1730Crossref PubMed Scopus (3995) Google Scholar). Globally, the mortality rate on dialysis is 10–15% per year, compared with 2–4% posttransplantation (2ERA-EDTA Registry. Patient Survival on Renal Replacement Therapy (RRT). ERA-EDTA Registry 2003 Annual Report. Amsterdam: ERA-EDTA Registry, 2005: 48-81. (Available at: http://www.eraedta.org)Google Scholar, 3McDonald SP, Excell L, Livingston B. Deaths. ANZDATA Registry Report 2005. In: McDonald S, Excel L, (eds). 26th annual report. Adelaide, South Australia: Australia and New Zealand Dialysis and Transplant Registry, 2005: xx-xxi. (Available at: http://www.anzdata.org.au)Google Scholar, 4U.S.Department of Health and Human Services. Kidney and Pancreas Transplantation Trends. 2005 Annual Report of the U. S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1995-2004. Rockville: Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, 2003: 9-10. (Available at: http://www.hrsa.gov/)Google Scholar). However, kidney transplantation is not without risk, as recipients are at increased risk of cardiovascular disease, cancer and infection and the relative mortality rate for kidney recipients after the first post‐transplant year remains 4–6 times that of the general population, with 33% deaths attributable to cardiovascular disease and 32% to cancer (3McDonald SP, Excell L, Livingston B. Deaths. ANZDATA Registry Report 2005. In: McDonald S, Excel L, (eds). 26th annual report. Adelaide, South Australia: Australia and New Zealand Dialysis and Transplant Registry, 2005: xx-xxi. 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Elevated cancer risk after transplantation is thought to result from the interplay of several factors: the chronic uraemic state favors carcinogenesis and overall or cumulative exposure to immunosuppression disrupts both anti‐tumor immunosurveillance and anti‐viral activity, and may potentiate the carcinogenic effects of other agents such as sunlight (7Cengiz K Block AM Hossfeld DK Anthone R Anthone S Sandberg AA Sister chromatid exchange and chromosome abnormalities in uremic patients.Cancer Genet Cytogenet. 1988; 36: 55-67Abstract Full Text PDF PubMed Scopus (44) Google Scholar, 8Birkeland SA Hamilton‐Dutoit S Is posttransplant lymphoproliferative disorder (PTLD) caused by any specific immunosuppressive drug or by the transplantation per se?.Transplantation. 2003; 76: 984-988Crossref PubMed Scopus (112) Google Scholar). Additionally, some drugs promote carcinogenesis by mechanisms independent of their immunosuppressive effects (9Buell JF Gross TG Woodle ES Malignancy after transplantation.Transplantation. 2005; 80: S254-S264Crossref PubMed Scopus (480) Google Scholar). Viral infections (including herpes and hepatitis viruses) are clearly linked to some malignancies and chronic antigen stimulation from the transplanted organ, repeated infections and transfusions of blood products have also been implicated. Quantifying an individual transplant, candidate's cancer risk informs pre‐transplant counseling, subsequent treatment decisions and has implications for monitoring, screening and follow‐up after transplantation (10Kiberd BA Keough‐Ryan T Clase CM Screening for prostate, breast and colorectal cancer in renal transplant recipients.Am J Transplant. 2003; 3: 619-625Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). Most previous published analyses of cancer risk after transplantation have concentrated on specific cancers (11Cherikh WS Kauffman HM McBride MA Maghirang J Swinnen LJ Hanto DW Association of the type of induction immunosuppression with posttransplant lymphoproliferative disorder, graft survival, and patient survival after primary kidney transplantation.Transplantation. 2003; 76: 1289-1293Crossref PubMed Scopus (262) Google Scholar, 12Dharnidharka VR Sullivan EK Stablein DM Tejani AH Harmon WE Risk factors for posttransplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation: A report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).Transplantation. 2001; 71: 1065-1068Crossref PubMed Scopus (194) Google Scholar, 13Vajdic CM McDonald SP McCredie MRE et al.Cancer Incidence Before and After Kidney Transplantation.JAMA. 2006; 296: 2823-2831Crossref PubMed Scopus (868) Google Scholar), or on risk associated with modifiable factors after the fact of transplantation, such as particular components of the immunosuppressive regimen employed (14Bustami RT Ojo AO Wolfe RA et al.Immunosuppression and the risk of post‐transplant malignancy among cadaveric first kidney transplant recipients.Am J Transplant. 2004; 4: 87-93Crossref PubMed Scopus (234) Google Scholar, 15Kauffman HM Cherikh WS Cheng Y Hanto DW Kahan BD Maintenance immunosuppression with target‐of‐rapamycin inhibitors is associated with a reduced incidence of de novo malignancies.Transplantation. 2005; 80: 883-889Crossref PubMed Scopus (553) Google Scholar), but have not fully elaborated the underlying epidemiology of malignancy in population. analyses are by their data to for all population on data all of may and Cancer after kidney transplantation in the J Transplant. 2004; 4: PubMed Scopus Google Scholar, SA et al.Cancer risk after renal transplantation in the J PubMed Scopus Google Scholar, SM AM Risk of in renal transplant PubMed Scopus Google Scholar). of were to the relative risk of cancer nonmelanocytic skin and lip cancer) in the post‐transplant population compared to that by the general population, and to risk the transplanted population, to absolute risk for post‐transplant cancer on recipient a at the of an of all and in the Australia and New Zealand Dialysis and Transplant Registry from the of first kidney ANZDATA is from the of the first of renal in Australia and New data on all patients for renal is have no of of kidney from the of their first renal and treatment cancer and cancer are Cancer are for and type using of for and are by with the data and data with are for patient for data and are for all data in and are also are identified the data are ANZDATA be on the cancer as any that to the cancer in Australia and New nonmelanocytic skin cancer, and in and lip not and skin cancers or and in at other as are not for the general population, without incidence data no with the transplant recipient lip as ANZDATA has that cancers at may have been Cancer report. In: McDonald SP, Excell L, (eds). ANZDATA Registry Report 2005. Adelaide, South Australia: Australia and New Zealand Dialysis and Transplant Registry, Scholar). were at of or but were not at the of transplant as that cancer risk was to graft previous has that dialysis is also associated with increased cancer risk over the general population, and the of was to and patients cancer risks at the of and for kidney transplantation graft and to dialysis are a CM McDonald SP McCredie MRE et al.Cancer Incidence Before and After Kidney Transplantation.JAMA. 2006; 296: 2823-2831Crossref PubMed Scopus (868) Google Scholar, R et of primary renal to end‐stage renal in the and from an J Kidney Full Text Full Text PDF PubMed Scopus Google Scholar, LJ et al.Cancer in patients PubMed Scopus Google Scholar). Rates of cancer were compared to the population, and standardized rate ratios (SRR with 95% calculated, first for all and by for the most using by year and general population incidence data were from the of Health and and for New Zealand were from the New Zealand Health and were from analyses were to transplant recipients with cancers the years to Cancer at the of Health and Cancer data Scholar). Within the transplanted population, risk factors and absolute risk of cancer were using survival for all patients on ANZDATA from with patients from the of transplantation the of their first post‐transplant cancer or Cancer risk factors the transplanted population were to factors to and patients at the of transplantation; primary underlying of year of transplantation, prior on dialysis, of prior malignancy and on dialysis and were and of transplantation was as a and at the year of of the and in immunosuppression in Australia and New of was and other previous published data have that with of are at risk, and with at risk of post‐transplant cancers (14Bustami RT Ojo AO Wolfe RA et al.Immunosuppression and the risk of post‐transplant malignancy among cadaveric first kidney transplant recipients.Am J Transplant. 2004; 4: 87-93Crossref PubMed Scopus (234) Google Scholar, Risk factors for cancer in renal transplant 1999; PubMed Scopus Google Scholar, et immunosuppression is an independent risk for some cancers in renal 2001; PubMed Scopus Google Scholar). of graft on cancer risk was using a from the of to of cancer were using ratios (HR with 95% an with post‐transplant cancer with on were a using the was with was using with as was using the and of was to the and to the of patients with cancer for different patient cancer risk was by the of the for the general population was using the by the of cancer for an equivalent general population and a of the cumulative analyses were using to a total of 15 183 people had a kidney transplant in Australia and New Zealand of (10.8%) developed at cancer, with cancers after graft the total were had had been to Australia and New of follow‐up per patient was years a total of of of graft transplantation was years 1 the of the total recipient of kidney transplant recipients with risks of with is for at of and renal on dialysis prior to 1 2 at = a of were not for all patients as have been by ANZDATA of risk is to 13 is for = a of were not for all patients as have been by ANZDATA of risk is to 13 in a the risk of cancer compared to the general population, transplant recipients were years at risk, developed at cancer. both and at all ages, the rates of cancer were elevated compared to in the general population, and are in and B. A transplant recipient aged 25 a rate of cancer equivalent to a in the general population compared with and a year recipient a rate equivalent to a compared with the was with recipients a rate of similar to a in the general population women with kidney times more cancers than women in the general population (SRR 95% for risk was and a (SRR 95% relative risk was not but was inversely related to the relative risk was by recipients of both with risk that by the general population with age 2 and relative risk of cancer for ANZDATA posttransplant population compared to the general population of Australia and New at cancer at rate by by sex and year, rate by by sex and year, in a rate ratios for cancers by age and for kidney transplant recipients in Australia and New Zealand Risk also by cancer relative risk of cancers by age and sex for the most cancers in the general population breast and and the most cancer in the transplant in the general and transplanted to and S, lymphoproliferative In: ES of of and Scholar). colorectal cancer in both risk the overall age trend and was the for with age (SRR and in years and years with similar trend for breast and cancer. for lymphoma, the of risk (SRR and for recipients and elevated risk of melanoma for and showed less variability across ages, and prostate cancer was not increased at cancer risk for kidney transplant by age and at cancer = in ANZDATA and = of cancers in and New Zealand general population of the age and sex over the = in ANZDATA and = of cancers in and New Zealand general population of the age and sex over the = in ANZDATA and = of cancers in and New Zealand general population of the age and sex over the = in ANZDATA and = of cancers in and New Zealand general population of the age and sex over the = in ANZDATA and = of cancers in and New Zealand general population of the age and sex over the = in ANZDATA and = of cancers in and New Zealand general population of the age and sex over the = in ANZDATA and = of cancers in and New Zealand general population of the age and sex over the = in ANZDATA and = of cancers in and New Zealand general population of the age and sex over the in the general and transplanted to and is with incidence in the general population, as data was not for New in the general and transplanted to and is with incidence in the general population, as data was not for New = in ANZDATA and = of cancers in and New Zealand general population of the age and sex over the in the general and transplanted to and is with incidence in the general population, as data was not for New in a Within the transplant population, to factors at the of transplant risk of subsequent analyses that all were associated with increased risk of cancer prior to transplantation (p = After for the effects of the other on dialysis prior to transplantation (p = (p = and (p = were no associated with post‐transplant cancer, and not was an age at transplantation and sex both affected cancer risk, was also an that risk was different for and but the of the as age at transplantation increased = age at transplantation, an age at transplantation and sex (p = 0.007), primary kidney disease (p = (p = prior malignancy (p = and the for graft (p = for all the and for the = risks of cancer after kidney transplantation are in with risk by age at transplantation for and were more than to be with a cancer if transplanted the age of years 95% the age of and was no sex and after the age of were more to be with a cancer their increased risk was not years 95% both and age at transplantation was associated with risk of post‐transplant cancer, but the risk for increased more as age at transplantation factors for cancer the kidney transplant are from the for age at transplantation, an age at transplantation and primary kidney disease, prior malignancy and the for graft at transplantation at transplantation at renal cancer at cancer graft are from the for age at transplantation, an age at transplantation and primary kidney disease, prior malignancy and the for graft in a was no cancer risk for recipients primary kidney disease was caused by or other but risk was reduced for had diabetic (HR 0.67; 95% 0.50–0.89). a similar increased risk for cancer as the of a prior malignancy (HR and and to dialysis reduced risk of subsequent cancer (HR cumulative risk of cancer for and from of transplantation are by age in and are for the effects of primary disease, prior cancer and the of graft cumulative risk in an and New Zealand general population of the age is also years in the general population more cancer than but in the transplant population the sex is more all age the the and to with from an general population. aged and a of patients have prior to transplantation, less cancer than be in the general population of the age for the years after transplantation, the increased malignancy risk by transplantation their incidence that in transplanted more cancer than transplanted the in not in the general population sex is among the epidemiology of cancer nonmelanocytic skin and lip cancer) in 15 183 kidney recipients transplanted over a for a of with the cancer of an equivalent general population, the relative risk by with was times than without and the of risk with age for recipients over the risk was times that of the general population. Rates of cancer in transplant recipients are equivalent to rates by people 20–30 years without and absolute the of cancer in the transplant population compared with the general population from in aged were compared to the in the general to in of were compared to and cancer risk for transplant recipients also from that in the general more than were of the cancers for all for breast and prostate cancers in the relative risks (SRR) in both by and across age groups Risk factors for cancer the transplanted population showed that women have a risk than transplanted at the but sex is for aged the risk is and for the age have increased risk cumulative risk is the sex is but not by the sex in the general population. of is that was on a of patients with a of follow‐up than any previous published CM McDonald SP McCredie MRE et al.Cancer Incidence Before and After Kidney Transplantation.JAMA. 2006; 296: 2823-2831Crossref PubMed Scopus (868) Google Scholar, RT Ojo AO Wolfe RA et al.Immunosuppression and the risk of post‐transplant malignancy among cadaveric first kidney transplant recipients.Am J Transplant. 2004; 4: 87-93Crossref PubMed Scopus (234) Google Scholar, Cancer after kidney transplantation in the J Transplant. 2004; 4: PubMed Scopus Google Scholar). Additionally, the of ANZDATA data the and the of the data that the a with and are transplant with of are less in the and on with for cancer and other data (14Bustami RT Ojo AO Wolfe RA et al.Immunosuppression and the risk of post‐transplant malignancy among cadaveric first kidney transplant recipients.Am J Transplant. 2004; 4: 87-93Crossref PubMed Scopus (234) Google Scholar, Cancer after kidney transplantation in the J Transplant. 2004; 4: PubMed Scopus Google Scholar, SA et al.Cancer risk after renal transplantation in the J PubMed Scopus Google Scholar, after renal transplantation: Dialysis and Transplantation Renal Dial Transplant. Scopus Google Scholar, Y Y Cancer incidence among kidney transplant recipients.Am J Transplant. PubMed Scopus Google Scholar). of risk with age at transplantation is in with other published other have that sex confers risk may be by the of of sex in in cancer epidemiology K to by Cancer PubMed Scopus Google Scholar, for and of Med. 2001; Scopus Google to the the effects of age at transplantation and sex on cancer risk has been CM McDonald SP McCredie MRE et al.Cancer Incidence Before and After Kidney Transplantation.JAMA. 2006; 296: 2823-2831Crossref PubMed Scopus (868) Google Scholar, RT Ojo AO Wolfe RA et al.Immunosuppression and the risk of post‐transplant malignancy among cadaveric first kidney transplant recipients.Am J Transplant. 2004; 4: 87-93Crossref PubMed Scopus (234) Google Scholar, Cancer after kidney transplantation in the J Transplant. 2004; 4: PubMed Scopus Google Scholar, Risk factors for cancer in renal transplant 1999; PubMed Scopus Google Scholar, Y Y Cancer incidence among kidney transplant recipients.Am J Transplant. PubMed Scopus Google Scholar, VB Risk of malignancy with immunosuppression in renal transplant 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, et of cancer after kidney from the North transplant 2003; 76: PubMed Scopus Google Scholar, J H B et al.Cancer risk transplantation: A in J 2003; PubMed Scopus Google Scholar). was caused by 32% less cancer than with from other remains and is in cancer risk for has been in at other published analyses and been (14Bustami RT Ojo AO Wolfe RA et al.Immunosuppression and the risk of post‐transplant malignancy among cadaveric first kidney transplant recipients.Am J Transplant. 2004; 4: 87-93Crossref PubMed Scopus (234) Google Scholar, Risk factors for cancer in renal transplant 1999; PubMed Scopus Google Scholar, VB Risk of malignancy with immunosuppression in renal transplant 2004; Full Text Full Text PDF PubMed Scopus Google Scholar), and is in to in the general population, have that with may be at risk of cancers H and cancer risk in and 2005; PubMed Scopus Google Scholar). may not have for in may be more to the of of other and of and be less to cancer. Additionally, of the of may be as have not recipients with from other than also have or as of the be by the in data of among the general population. of race on cancer risk in transplant recipients has been in analyses from American risk in and relative to American (14Bustami RT Ojo AO Wolfe RA et al.Immunosuppression and the risk of post‐transplant malignancy among cadaveric first kidney transplant recipients.Am J Transplant. 2004; 4: 87-93Crossref PubMed Scopus (234) Google Scholar, Cancer after kidney transplantation in the J Transplant. 2004; 4: PubMed Scopus Google Scholar). Australia and New the population with and to the population. groups may have reduced incidence of breast and prostate cancers compared to the general population T Y Cancer incidence and survival for in the J 2005; PubMed Scopus Google Scholar), and the transplanted population also have reduced graft and overall survival, both of may to SP Survival of recipients of cadaveric kidney compared with dialysis treatment in Australia and New Dial Transplant. PubMed Scopus Google Scholar). race as a for or factors that may cancer risk is also but to with data was ANZDATA to data of that the of the risk for be has been risk to and to risk to has the for quality and the of absolute and not relative risks A for to 2003; PubMed Scopus Google Scholar, H of 2003; PubMed Scopus Google Scholar, J to patients 2003; PubMed Scopus Google Scholar). to and the in 5 patients with a of the of with malignancy after transplantation a risk to their individual than the more 1 in white women transplanted the age of with no prior of a cancer and a graft for 10 years a cancer, to 1 in white with a prior of cancer transplanted aged or but with from the aged 45–54 at transplantation with graft at 10 years have cancer risks varying from in 13 (non‐white, diabetic no prior cancer) to in (white, prior cancer, from other absolute risk of a cancer per kidney recipients at 5 and 10 years after transplantation for different patient renal cancer at transplantation at transplantation renal cancer at transplantation 45–54 at transplantation in a A of a cancer risk from the of transplantation to factors that are to such as the immunosuppressive drug and may also have implications for post‐transplant and the of in the of and practice guidelines among also that guidelines may and American guidelines screening for prostate cancer with prostate specific antigen for all transplant recipients over the age of S et of renal transplantation Clinical practice J Transplant. 2001; Google Scholar, on Renal practice guidelines for renal of the transplant Cancer risk after renal and Dial Transplant. Scholar), but or reduced risk of prostate cancer compared to the general population, and the on is not screening the general population or not to that is a 2005; PubMed Scopus Google Scholar, S J Screening for prostate 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). and American guidelines also for recipients over of the general population of similar age has mortality J et of screening in and on A 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). However, that the risks for transplant recipients relative to the general population are at A more breast cancer treatment and survival in the transplant population may be to screening has similar for all ages, and if the mortality in the general population be for with rates of cancer in kidney recipients are similar to nontransplanted people 20–30 years older, but the transplanted population cancer relative and absolute risk differs across patient groups on primary of prior malignancy and graft have to of risk on patient transplantation, to and subsequent post‐transplant