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Incidence of Cancer in Kidney Transplantation Waiting List Patients: A Single Center Experience
Incidence of Cancer in Kidney Transplantation Waiting List Patients: A Single Center Experience G. Mosconi, L. Stalteri, F. Centofanti, I. Capelli, E. Carretta, E. Persici, G. Ubaldi, G. Battaglino, C. Raimondi, M.P. Scolari, and S. Stefoni ABSTRACT Introduction. It is widely accepted that the risk of malignancies is significantly increased among patients with end-stage kidney disease (ESKD) and after kidney transplantation compared with the general population. Only a few data are available on kidney transplantation waiting list patients. The aim of this study was to investigate solid organ cancer incidence among subjects on the waiting list at a single center. Materials and Methods. We retrospectively reviewed the records of all patients enrolled on our kidney transplantation waiting list between August 1, 2008 and July 31, 2010, seeking to evaluate the causes of withdrawal from the list, incidence of cancer, type of neoplasm, and its correlation with clinical features. We estimated the ratio of observed to expected numbers of cancers, the standardized incidence ratio (SIR). Results. Among 1184 patients, we excluded 569 patients from the waiting list including 26 (4.56%) who displayed malignancies. The overall incidence of cancer was 0.11 events/person-months and the overall prevalence of cancer was 2.2%. In 97% of patients, the malignant disease was confined to the primitive organ of origin without secondary dissemination. We observed a prevalence of cancers related to ESKD (17; 65.38%). The SIR for all cancer types in our population compared with the general population was 2.22. The SIR for native kidney and thyroid cancers among our population compared with the general population was ⬎10. Conclusion. The incidence of cancer was significantly increased among kidney transplantation waiting list patients compared with the general population. Our study highlighted the importance of a careful, targeted neoplastic screening. It could be particularly important for ESKD-related malignancies like native kidney tumors or thyroid cancers. HE RISK of malignancies after kidney transplantation is widely accepted to be significantly increased compared with the general population,1,2 possibly due to immunosuppression and viral infections acting as additional neoplastic risk factors to the traditional ones. The incidence of cancer is also increased in end-stage kidney disease (ESKD) and hemodialysis patients compared with the general population, albeit that it is lower than among transplant recipients.3,4 Although the pathogenesis is still unclear, this finding may be attributed to advanced renal pathology and systemic effects of reduced kidney function. Several factors seem to be involved in malignant transformation and tumor formation5: impaired immune system function; reduced antioxidant defenses with increased formation of reactive oxygen species; parathyroid hormone
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excess and deficiency of 1,25-Dihydroxycholecalciferol; chronic infection and inflammation; immunosuppressive medications during the course of glomerulonephritis or a previous kidney transplantation; and accumulation of carcinogenic compounds and chronic exposure to uremic toxins. There are also other factors directly related to From the Section of Nephrology (G.M., L.S., F.C., I.C., E.C., E.P., G.U., G.B., C.R., M.P.S., S.S.), Department of Internal Medicine, Aging and Renal Disease, St. Orsola Hospital, and Department of Medicine and Public Health (E.C.), University of Bologna, Bologna, Italy. Address reprint requests to G. Mosconi, Section of Nephrology, Department of Internal Medicine, Aging and Renal Disease, St. Orsola Hospital, University of Bologna, 40128 Bologna, Italy.
© 2011 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter doi:10.1016/j.transproceed.2011.01.121
Transplantation Proceedings, 43, 1003–1005 (2011)
1003
1004
hemodialysis treatments, such as the following: bioincompatibility reactions due to complement-activating dialysis membrances and impaired DNA repair. Moreover, dialysis patients show high cumulative levels of radiation exposure related to frequent radiographic procedures.6 Despite the higher incidence, ESKD patients are not more likely to present in late stages of malignancies compared with the general population. This observation is partial due to the frequent medical, laboratory, and instrumental evaluations of these patients.7 The literature describes only a few experiences regarding kidney transplantation waiting list patients who require an accurate neoplastic screening because of their higher cancer risk posttransplantation. The aim of this study was to analyze the cancer incidence among the waiting list for renal transplantation. MATERIALS AND METHODS We retrospectively observed the records of all patients enrolled on the transplantation waiting list between August 1, 2008 and July 31, 2010. They were all older than 18 years of age and scheduled to receive a graft from a deceased donor. We analyzed the various causes of withdrawal from the waiting list, including onset of a solid organ tumor, as well as the incidence and type of cancer pathology, and the correlation between cancer onset and clinical features. Cancers were grouped3,8 according to whether they were or were not related to ESKD or immunodeficiency, namely, whether it is increased among persons with human immunodeficiency virus (HIV) as well as in transplant recipients.9 The remaining cancers were categorized as “of uncertain status.” No cancer was excluded or included in more than one category. Data analysis was performed using commercially available statistical software SAS 9.1 (SAS Institute, Cary, NC, United States). The results are presented as mean values ⫾ standard deviations, unless otherwise stated. The differences between groups were assessed by chi-square or Fisher exact tests, as appropriate. P ⬍ .05 was considered statistically significant. The ratio of observed to expected numbers of cancers, the standardized incidence ratio (SIR), was estimated with 95% confidence intervals (CIs). To calculate expected numbers of cancers, we obtained incidence rates by age in 5-year groups and by gender for all Italians using data from 2000 –2003 (http://www.registri-tumori.it).
MOSCONI, STALTERI, CENTOFANTI ET AL
months/person (0.11 months/person for patients awaiting a first and 0.13 months/person for those awaiting a second kidney transplantation. The overall prevalence of cancer was 2.2% 2.09% among patients awaiting a first versus, 2.63% for those awaiting a second kidney transplantation. The detected malignancies were as follows: thyroid cancers (n ⫽ 9), tumors of the native kidney (n ⫽ 8), testicular germinoma (n ⫽ 1), rectal (n ⫽ 1), lung (n ⫽ 1), ovary (n ⫽ 1), breast (n ⫽ 2), stomach (n ⫽ 2) or central nervous system (n ⫽ 1) tumors. In 25/26 patients, the malignant disease was confined to the primitive organ of origin, without secondary dissemination. Gender and age did not significantly correlate with type of cancer; patients who had undergone a previous transplantation showed a higher not significant incidence of cancer. According to the classification proposed by Vajdic et al,8 we observed a greater prevalence of cancers related to ESKD (17; 65.38%) versus those related to immune deficiency (3; 11.53%), or not related to immune deficiency (4; 15.38%) or cancers of uncertain status (2; 7.69%; Fig 1). The SIR for all cancer types among our patients compared with the general population was 2.22 (95% CI, 1.48 –3.07). The SIR for native kidney and thyroid cancers among our population compared with the general population was ⬎10. DISCUSSION
ESKD patients present a greater incidence of cancers than that observed among the general population, particularly for tumors of the native kidney, prostate, thyroid, liver, uterine, and lymphoma. Transplantation is associated with a considerably greater cancer incidence, perhaps due to long-term exposure to immunosuppressive therapies. In particular, there is an excessive incidence of virus-associated cancers among this category of patients. Few data are available about kidney transplantation waiting list patients. Our results showed an epidemiological importance of cancer incidence (0.11 months/person) and prevalence (2.2%) in this population who showed an increased risk of neoplastic diseases compared with the general population, namely a SIR ⬎2. The incidence and prevalence of malig-
RESULTS
Our 1184 patients, including 735 males and 449 females, had an overall mean age of 50.1 ⫾ 10.6 years (range, 16 –75). There were 956 awaiting a first and 228 awaiting a second kidney transplantation. During the followup period, 569 patients withdrew from the waiting list, including 370 patients who underwent a kidney transplantation (65.02%), 27 (4.74%) died 87 because of the patient’s decision (15.32%), and 59 were not suitable due to a clinical or surgical reason (10.36%). The 26 (4.56%) who presented with a neoplastic disease included 13 males and 13 females of overall mean age of 48.6 ⫾ 10.9 years. Six of the 26 patients, namely 4 males and 2 females of overall mean age of 49 ⫾ 13 years had previously received a kidney transplant with a prior mean duration of immunosuppressive therapy of 57 ⫾ 79 months. The overall incidence of cancer was 0.11
Fig 1. According to the classification proposed by Vajdic et al,8 we subdivided cancers into related to ESKD, related to immunodeficiency, not related to immunodeficiency, and cancers of uncertain status, and we observed the subsequent percentage: 65.38%, 11.53%, 15.38%, and 7.69%, respectively.
INCIDENCE OF CANCER
nancies did not appear to be related to the age of patients. Our results underline the need for accurate cancer screening also in young kidney transplantation waiting list patients. We observed an increased incidence of ESKDrelated cancers (Fig 1), in particular for native kidney cancers and thyroid cancers. Oxidant injury and oxalate accumulation have been proposed to be pathogenetic factors for the onset of native kidney tumors in ESKD patients with acquired cystic disease. Indeed, scarring and cyst formation occur as a consequence of renal failure, and elevated oxalate blood levels are due to reduced clearance. A vectorial transportation of oxalate occurs across the tubular epithelium leading to accumulation in the kidney. It crystallizes, inducing oxidant injury with as yet unknown genomic damage leading to cystic epithelial hyperplasia and tumor formation.10 With the aim of excluding neoplastic degeneration of a renal cyst, instrumental monitoring of the native kidney seems useful. In our center, we performed ultrasonographic abdominal examinations before inscription on the waiting list and then every year thereafter. In the case of polycystic disease, we used computed tomography or magnetic resonance examination. The increased thyroid cancer stems from reduced production of the selenocysteine-containg enzyme, glutathione-peroxidase, either, due to damage to the proximal tubular epithelium, the main source of the circulating form of the enzyme, or due to uremia-related selenium deficiency.3,5 In our center we evaluate regularly secondary hyperparathyroidism with an ultrasonographic examination of the parathyroid glands. This clinical practice may have influenced the greater number of diagnosed thyroid cancers. We suggest adding to the recommendation of palpation and visual inspection of the thyroid gland11,12 an instrumental monitoring of this organ. We prescribe an ultrasonographic examination before inscription on the waiting list and then every 2 years thereafter. In cases of solid formations we suggest a fine needle biopsy. In light of the impact of these neoplastic diseases on our population, we believe that this instrumental follow-up has a favorable cost-benefit ratio. In our experience we did not observe hematologic malignancies. We hypothesized that there tumors were subjected to a higher degree of selection before patient referral, although it does not completely explain the low incidence among our population. Almost all patients presenting a cancer pathology showed it to be confined to the primitive organ without any secondary involvement. This observation may be related to the accurate screening tests that these patients undergo for
1005
kidney transplantation waiting list inscription and maintenance. An early diagnosis of cancer disease may be important for patient survival. It also permits the best transplantation opportunities and easier management of the list. It is indeed important to focus on the fact that cancer therapy is considerably less complicated among ESKD compared with transplant recipients. This study was limited to reporting a single-center experience. Other larger, multicenter studies with longer follow-up periods are needed to confirm our findings to understand whether different clinical practices may influence the patterns of solid organ tumors. In conclusion, our single-center experience showed the importance of careful screening for cancer at the moment of enrollment and during maintenance on the kidney transplantation waiting list. An early diagnosis and treatment of malignancies is necessary for optimal management of waiting lists. In our opinion we must focus attention and resources on ESKD-related tumors, considering their elevated incidence among this population. REFERENCES 1. Webster AC, Craig JC, Simpson JM, et al: Identifying high risk groups and quantifying absolute risk of cancer after kidney transplantation: a cohort study of 15,183 recipients. Am J Transplant 7:2140, 2007 (Epub July 19, 2007) 2. Campistol JM, Albanell J, Arns W, et al: Use of proliferation signal inhibitors in the management of post-transplant malignancies:clinical guidance. Nephrol Dial Transplant 22(suppl 1):i36, 2007 3. Stewart JH, Vajdic CM, van Leeuwen MT, et al: The pattern of excess cancer in dialysis and transplantation. Nephrol Dial Transplant 24:3225, 2009 4. Mandayam S, Shahinian VB: Are chronic dialysis patients at increased risk for cancer? J Nephrol 21:166, 2008 5. Vamvakas S, Bahner U, Heidland A: Cancer in end-stage renal disease: potential factors involved. Am J Nephrol 18:89, 1998 6. Kinsella SM, Coyle JP, Long EB, et al: Maintenance hemodialysis patients have high cumulative radiation exposure. Kidney Int 78:789, 2010 7. Taneja S, Mandayam S, Kayani ZZ, et al: Comparison of stage at diagnosis of cancer in patients who are on dialysis versus the general population. Clin J Am Soc Nephrol 2:1008, 2007 8. Vajdic CM, McDonald SP, McCredie MRE, et al: Cancer incidence before and after kidney transplantation. JAMA 296: 2823, 2006 9. Grulich AE, van Leeuwen MT, Falster MO, et al: Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 370:59, 2007 10. Fleming S: Renal cell carcinoma in acquired cystic kidney disease. Histopathology 56:395, 2010 11. Fischereder M, Jauch KW: Prevalence of cancer history prior to renal transplantation. Transplant Int 18:779, 2005 12. Kasiske BL, Cangro CB, Hariharan S, et al: The evaluation of renal transplant candidates: clinical practice guidelines. Am J Transplant 2(suppl 1):5, 2001
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excess and deficiency of 1,25-Dihydroxycholecalciferol; chronic infection and inflammation; immunosuppressive medications during the course of glomerulonephritis or a previous kidney transplantation; and accumulation of carcinogenic compounds and chronic exposure to uremic toxins. There are also other factors directly related to From the Section of Nephrology (G.M., L.S., F.C., I.C., E.C., E.P., G.U., G.B., C.R., M.P.S., S.S.), Department of Internal Medicine, Aging and Renal Disease, St. Orsola Hospital, and Department of Medicine and Public Health (E.C.), University of Bologna, Bologna, Italy. Address reprint requests to G. Mosconi, Section of Nephrology, Department of Internal Medicine, Aging and Renal Disease, St. Orsola Hospital, University of Bologna, 40128 Bologna, Italy.
© 2011 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter doi:10.1016/j.transproceed.2011.01.121
Transplantation Proceedings, 43, 1003–1005 (2011)
1003
1004
hemodialysis treatments, such as the following: bioincompatibility reactions due to complement-activating dialysis membrances and impaired DNA repair. Moreover, dialysis patients show high cumulative levels of radiation exposure related to frequent radiographic procedures.6 Despite the higher incidence, ESKD patients are not more likely to present in late stages of malignancies compared with the general population. This observation is partial due to the frequent medical, laboratory, and instrumental evaluations of these patients.7 The literature describes only a few experiences regarding kidney transplantation waiting list patients who require an accurate neoplastic screening because of their higher cancer risk posttransplantation. The aim of this study was to analyze the cancer incidence among the waiting list for renal transplantation. MATERIALS AND METHODS We retrospectively observed the records of all patients enrolled on the transplantation waiting list between August 1, 2008 and July 31, 2010. They were all older than 18 years of age and scheduled to receive a graft from a deceased donor. We analyzed the various causes of withdrawal from the waiting list, including onset of a solid organ tumor, as well as the incidence and type of cancer pathology, and the correlation between cancer onset and clinical features. Cancers were grouped3,8 according to whether they were or were not related to ESKD or immunodeficiency, namely, whether it is increased among persons with human immunodeficiency virus (HIV) as well as in transplant recipients.9 The remaining cancers were categorized as “of uncertain status.” No cancer was excluded or included in more than one category. Data analysis was performed using commercially available statistical software SAS 9.1 (SAS Institute, Cary, NC, United States). The results are presented as mean values ⫾ standard deviations, unless otherwise stated. The differences between groups were assessed by chi-square or Fisher exact tests, as appropriate. P ⬍ .05 was considered statistically significant. The ratio of observed to expected numbers of cancers, the standardized incidence ratio (SIR), was estimated with 95% confidence intervals (CIs). To calculate expected numbers of cancers, we obtained incidence rates by age in 5-year groups and by gender for all Italians using data from 2000 –2003 (http://www.registri-tumori.it).
MOSCONI, STALTERI, CENTOFANTI ET AL
months/person (0.11 months/person for patients awaiting a first and 0.13 months/person for those awaiting a second kidney transplantation. The overall prevalence of cancer was 2.2% 2.09% among patients awaiting a first versus, 2.63% for those awaiting a second kidney transplantation. The detected malignancies were as follows: thyroid cancers (n ⫽ 9), tumors of the native kidney (n ⫽ 8), testicular germinoma (n ⫽ 1), rectal (n ⫽ 1), lung (n ⫽ 1), ovary (n ⫽ 1), breast (n ⫽ 2), stomach (n ⫽ 2) or central nervous system (n ⫽ 1) tumors. In 25/26 patients, the malignant disease was confined to the primitive organ of origin, without secondary dissemination. Gender and age did not significantly correlate with type of cancer; patients who had undergone a previous transplantation showed a higher not significant incidence of cancer. According to the classification proposed by Vajdic et al,8 we observed a greater prevalence of cancers related to ESKD (17; 65.38%) versus those related to immune deficiency (3; 11.53%), or not related to immune deficiency (4; 15.38%) or cancers of uncertain status (2; 7.69%; Fig 1). The SIR for all cancer types among our patients compared with the general population was 2.22 (95% CI, 1.48 –3.07). The SIR for native kidney and thyroid cancers among our population compared with the general population was ⬎10. DISCUSSION
ESKD patients present a greater incidence of cancers than that observed among the general population, particularly for tumors of the native kidney, prostate, thyroid, liver, uterine, and lymphoma. Transplantation is associated with a considerably greater cancer incidence, perhaps due to long-term exposure to immunosuppressive therapies. In particular, there is an excessive incidence of virus-associated cancers among this category of patients. Few data are available about kidney transplantation waiting list patients. Our results showed an epidemiological importance of cancer incidence (0.11 months/person) and prevalence (2.2%) in this population who showed an increased risk of neoplastic diseases compared with the general population, namely a SIR ⬎2. The incidence and prevalence of malig-
RESULTS
Our 1184 patients, including 735 males and 449 females, had an overall mean age of 50.1 ⫾ 10.6 years (range, 16 –75). There were 956 awaiting a first and 228 awaiting a second kidney transplantation. During the followup period, 569 patients withdrew from the waiting list, including 370 patients who underwent a kidney transplantation (65.02%), 27 (4.74%) died 87 because of the patient’s decision (15.32%), and 59 were not suitable due to a clinical or surgical reason (10.36%). The 26 (4.56%) who presented with a neoplastic disease included 13 males and 13 females of overall mean age of 48.6 ⫾ 10.9 years. Six of the 26 patients, namely 4 males and 2 females of overall mean age of 49 ⫾ 13 years had previously received a kidney transplant with a prior mean duration of immunosuppressive therapy of 57 ⫾ 79 months. The overall incidence of cancer was 0.11
Fig 1. According to the classification proposed by Vajdic et al,8 we subdivided cancers into related to ESKD, related to immunodeficiency, not related to immunodeficiency, and cancers of uncertain status, and we observed the subsequent percentage: 65.38%, 11.53%, 15.38%, and 7.69%, respectively.
INCIDENCE OF CANCER
nancies did not appear to be related to the age of patients. Our results underline the need for accurate cancer screening also in young kidney transplantation waiting list patients. We observed an increased incidence of ESKDrelated cancers (Fig 1), in particular for native kidney cancers and thyroid cancers. Oxidant injury and oxalate accumulation have been proposed to be pathogenetic factors for the onset of native kidney tumors in ESKD patients with acquired cystic disease. Indeed, scarring and cyst formation occur as a consequence of renal failure, and elevated oxalate blood levels are due to reduced clearance. A vectorial transportation of oxalate occurs across the tubular epithelium leading to accumulation in the kidney. It crystallizes, inducing oxidant injury with as yet unknown genomic damage leading to cystic epithelial hyperplasia and tumor formation.10 With the aim of excluding neoplastic degeneration of a renal cyst, instrumental monitoring of the native kidney seems useful. In our center, we performed ultrasonographic abdominal examinations before inscription on the waiting list and then every year thereafter. In the case of polycystic disease, we used computed tomography or magnetic resonance examination. The increased thyroid cancer stems from reduced production of the selenocysteine-containg enzyme, glutathione-peroxidase, either, due to damage to the proximal tubular epithelium, the main source of the circulating form of the enzyme, or due to uremia-related selenium deficiency.3,5 In our center we evaluate regularly secondary hyperparathyroidism with an ultrasonographic examination of the parathyroid glands. This clinical practice may have influenced the greater number of diagnosed thyroid cancers. We suggest adding to the recommendation of palpation and visual inspection of the thyroid gland11,12 an instrumental monitoring of this organ. We prescribe an ultrasonographic examination before inscription on the waiting list and then every 2 years thereafter. In cases of solid formations we suggest a fine needle biopsy. In light of the impact of these neoplastic diseases on our population, we believe that this instrumental follow-up has a favorable cost-benefit ratio. In our experience we did not observe hematologic malignancies. We hypothesized that there tumors were subjected to a higher degree of selection before patient referral, although it does not completely explain the low incidence among our population. Almost all patients presenting a cancer pathology showed it to be confined to the primitive organ without any secondary involvement. This observation may be related to the accurate screening tests that these patients undergo for
1005
kidney transplantation waiting list inscription and maintenance. An early diagnosis of cancer disease may be important for patient survival. It also permits the best transplantation opportunities and easier management of the list. It is indeed important to focus on the fact that cancer therapy is considerably less complicated among ESKD compared with transplant recipients. This study was limited to reporting a single-center experience. Other larger, multicenter studies with longer follow-up periods are needed to confirm our findings to understand whether different clinical practices may influence the patterns of solid organ tumors. In conclusion, our single-center experience showed the importance of careful screening for cancer at the moment of enrollment and during maintenance on the kidney transplantation waiting list. An early diagnosis and treatment of malignancies is necessary for optimal management of waiting lists. In our opinion we must focus attention and resources on ESKD-related tumors, considering their elevated incidence among this population. REFERENCES 1. Webster AC, Craig JC, Simpson JM, et al: Identifying high risk groups and quantifying absolute risk of cancer after kidney transplantation: a cohort study of 15,183 recipients. Am J Transplant 7:2140, 2007 (Epub July 19, 2007) 2. Campistol JM, Albanell J, Arns W, et al: Use of proliferation signal inhibitors in the management of post-transplant malignancies:clinical guidance. Nephrol Dial Transplant 22(suppl 1):i36, 2007 3. Stewart JH, Vajdic CM, van Leeuwen MT, et al: The pattern of excess cancer in dialysis and transplantation. Nephrol Dial Transplant 24:3225, 2009 4. Mandayam S, Shahinian VB: Are chronic dialysis patients at increased risk for cancer? J Nephrol 21:166, 2008 5. Vamvakas S, Bahner U, Heidland A: Cancer in end-stage renal disease: potential factors involved. Am J Nephrol 18:89, 1998 6. Kinsella SM, Coyle JP, Long EB, et al: Maintenance hemodialysis patients have high cumulative radiation exposure. Kidney Int 78:789, 2010 7. Taneja S, Mandayam S, Kayani ZZ, et al: Comparison of stage at diagnosis of cancer in patients who are on dialysis versus the general population. Clin J Am Soc Nephrol 2:1008, 2007 8. Vajdic CM, McDonald SP, McCredie MRE, et al: Cancer incidence before and after kidney transplantation. JAMA 296: 2823, 2006 9. Grulich AE, van Leeuwen MT, Falster MO, et al: Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 370:59, 2007 10. Fleming S: Renal cell carcinoma in acquired cystic kidney disease. Histopathology 56:395, 2010 11. Fischereder M, Jauch KW: Prevalence of cancer history prior to renal transplantation. Transplant Int 18:779, 2005 12. Kasiske BL, Cangro CB, Hariharan S, et al: The evaluation of renal transplant candidates: clinical practice guidelines. Am J Transplant 2(suppl 1):5, 2001