Incidence and spectrum of dialysis-associated cancer in three continents
2000; Elsevier BV; Volume: 35; Issue: 2 Linguagem: Inglês
10.1016/s0272-6386(00)70349-0
ISSN1523-6838
AutoresA. Heidland, Udo Bahner, Spiros Vamvakas,
Tópico(s)Dialysis and Renal Disease Management
ResumoThis month's discussion. . .The Journal Club focuses on an article entitled “Cancer in Patients on Dialysis for End-Stage Renal Disease: An International Collaborative Study” (Lancet 354:93-99, 1999) by Patrick Maisonneuve, Lawrence Agodoa, Ryszard Gellert, John H. Stewart, Gherardo Buccianti, Albert B. Lowenfels, Robert A. Wolfe, Elisabeth Jones, Alex P.S. Disney, Douglas Briggs, Margaret McCredie, and Peter Boyle.Recently, a large international collaborative study on cancer in patients on dialysis for end-stage renal disease was published by Patrick Maisonneuve and colleagues1Maisonneuve P Agodoa L Gellert R Stewart JH Buccianti G Lowenfels AB Wolfe RA Jones E Disney APS Briggs D McCredie M Boyle P Cancer in patients on dialysis for end-stage renal disease: An international collaborative study.Lancet. 1999; 354: 93-99Google Scholar in The Lancet (July 10, 1999). By use of dialysis registries from the United States, Europe, and Australia/New Zealand, a cohort of 831,804 patients in the period from 1980 to 1994 was assembled and the observed number of cancer matched with the respective background population.Fig 2SIR of the major cancer sites in patients on dialysis in three continents (data from Maisonneuve et al1Maisonneuve P Agodoa L Gellert R Stewart JH Buccianti G Lowenfels AB Wolfe RA Jones E Disney APS Briggs D McCredie M Boyle P Cancer in patients on dialysis for end-stage renal disease: An international collaborative study.Lancet. 1999; 354: 93-99Google Scholar).View Large Image Figure ViewerDownload Hi-res image Download (PPT)The raised overall risk of cancer in dialysis demonstrated in the collaborative study confirms and extends numerous earlier reports in smaller patient groups.2Port FK Ragheb NE Schwartz AG Hawthorne VM Neoplasms in dialysis patients: A population-based study.Am J Kidney Dis. 1989; 14: 119-123Google Scholar, 3Inamoto H Ozaki R Matsuzaki T Wakui M Saruta T Osawa A Incidence and mortality patterns of malignancy and factors affecting the risk of malignancy in dialysis patients.Nephron. 1991; 59: 611-617Google Scholar, 4Iseki K Osawa A Fukiyama K Evidence for increased cancer deaths in chronic dialysis patients.Am J Kidney Dis. 1993; 22: 308-313Google Scholar, 5Pope JC Koch MO Bluth RF Renal cell carcinoma in patients with end-stage renal disease: A comparison of clinical significance in patients receiving haemodialysis and those with renal transplants.Urology. 1994; 44: 497-501Google Scholar, 6Cuckovic C Djukanovic L Jankovic S Stanojcic A Dragicevic P Radmilovic A Lambic L Stojanovic M Milic M Bakovic J Radovic M Labudovic M Malignant tumors in hemodialysis patients.Nephron. 1996; 73: 710-712Google Scholar, 7Buccianti G Maisonneuve P Ravasi B Cresseri D Locatelli F Boyle P Cancer among patients on renal replacement therapy: A population-based survey in Lombardy, Italy.Int J Cancer. 1996; 66: 591-593Google Scholar It has to be stressed that inclusion of cancer patients of the predialysis period would have further increased the prevalence of cancer. Thus, in this study, a total of 47,866 patients (corresponding nearly to a twofold higher number of cancer patients in dialysis) with the previous diagnosis of cancer or those whose primary renal disease was attributed to malignancies or amyloidosis were excluded. There is evidence that the risk of cancer is already enhanced in pre–end-stage renal disease. Also in the collaborative study, the high incidence of malignancies within the first year of dialysis (as compared with the following years) underlines the importance of the predialysis period for the development of cancer, because most cancer types have latency periods of several years. The excessive overall incidence of cancer in the dialysis population of Australia/New Zealand is explained by the authors with a more accurate documentation in these countries, whereas registries of Europe and the United States may have been less complete. This is supported by the fact that in some European countries with a more precise documentation such as Sweden, Denmark, and The Netherlands, cancer prevalence in dialysis is comparable to that of Australia/New Zealand.1Maisonneuve P Agodoa L Gellert R Stewart JH Buccianti G Lowenfels AB Wolfe RA Jones E Disney APS Briggs D McCredie M Boyle P Cancer in patients on dialysis for end-stage renal disease: An international collaborative study.Lancet. 1999; 354: 93-99Google ScholarEnhanced cancer formation involved in particular the kidney and was positively related to the length of time on dialysis treatment and negatively to patients' age at the beginning of renal replacement therapy. Malignancies of the kidney were associated in high percentage with toxic nephropathy, but also with glomerulonephritis and arteriopathy. Several lines of evidence point to a causal relation between renal cell cancer and acquired renal cystic disease, which increases strikingly during long-term dialysis therapy.8Marple JT Mac Dougall M Chonko AM Renal cancer complicating acquired cystic kidney disease.J Am Soc Nephrol. 1994; 4: 1951-1956Google Scholar, 9Chudek J Herbers J Wilhelm M Kenck C Bugert P Ritz E Waldman F Kovacs G The genetics of renal tumors in end-stage renal failure differs from those occurring in the general population.J Am Soc Nephrol. 1998; 9: 1045-1051Google Scholar In its pathogenesis, the toxic effects of uremia are implicated, because after kidney transplantation, incidence of renal cysts and cancer is less frequent in the native kidneys.10Pecqueux JC Schwarz A Dieckmann KP Offermann G Cancer incidence in patients on chronic dialysis and in renal transplant recipients.Urol Int. 1990; 45: 290-292Google Scholar Analgesic abuse, the other contributor of renal cell carcinoma, has an especially high prevalence in Australia.1Maisonneuve P Agodoa L Gellert R Stewart JH Buccianti G Lowenfels AB Wolfe RA Jones E Disney APS Briggs D McCredie M Boyle P Cancer in patients on dialysis for end-stage renal disease: An international collaborative study.Lancet. 1999; 354: 93-99Google ScholarFurthermore, a high incidence of tumors of the bladder was observed associated with infectious, obstructive, and toxic nephropathies. The risk of bladder cancer was unrelated to duration of dialysis treatment. In end-stage renal disease, the slower transit of the urine with high content of toxic waste products could be involved in the pathogenesis of bladder cancer.A surprising observation is a high time-dependent increase of thyroid carcinoma in the dialysis patients. In the pathogenesis of thyroid cancer, enhanced formation of free radicals and an impaired scavenger system, in particular due to a decreased selenium level of the gland, is discussed.11Köhrle J Schmutzler C Fekete H Dreher I Goretzki P Simon D Gawlik D Behne D Brabant G The role of selenium in human thyroid carcinoma.Exp Clin Endocrinol. 1995; 103 (abstr): 117AGoogle Scholar It is conceivable that in uremia, the enhanced formation of reactive oxygen species in the presence of the frequently lowered plasma levels of the selenium and glutathione peroxidase12Bonomini M Albertazzi A Selenium in uremia.Artif Organs. 1995; 19: 413-448Google Scholar contribute to cancer development of the thyroid.Other types of enhanced cancer risk in the collaborative study were linked to infections with oncogenic viruses such as carcinoma of the tongue (human papilloma virus 16 [HPV-16]), cervix uteri (HPV-16 and HPV-18), and liver (hepatitis B and C virus infection). Also in Hodgkin's disease, the causal role of viral infection (Epstein-Barr virus [EBV]) is assumed. Recently, reactivation of EBV infection during long-term hemodialysis therapy has been described.13Winkelspecht B Müller-Lantzsch N Kohler H Serological evidence for reactivation of EBV infection due to uraemic immunodeficiency.Nephrol Dial Transplant. 1997; 12: 2099-2104Google ScholarEven in multiple myeloma there are hints for the involvement of virus infection. Thus, Kaposi's sarcoma–associated herpesvirus (KSHV) infection of bone marrow dendritic cells has been demonstrated in some myeloma patients.14Rettig MB Ma HJ Vescio RA Pöld M Schiller G Belson D Savage A Nishikubo C Wu C Fraser J Said JW Berenson JR Kaposi's sarcoma-associated herpesvirus infection of bone marrow dendritic cells from multiple myeloma patients.Science. 1997; 276: 1851-1854Google Scholar In the genome of KSHV, a homolog of human interleukin-6 (IL-6) could be identified.15Moore PS Boshoff C Weiss RA Chang Y Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV.Science. 1996; 274: 1739-1744Google Scholar It is interesting that IL-6, which is markedly enhanced in the plasma of dialysis patients, is a growth factor for myeloma cells due to both stimulation of cell growth and prevention of apoptosis.16Kishimoto T Akira S Taga T Interleukin-6 and its receptor: A paradigm for cytokines.Science. 1992; 258: 593-597Google Scholar However, it is unlikely that enhanced plasma levels of IL-6 in uremia play a causal role in the pathogenesis of myeloma with regard to its rare occurrence in end-stage renal failure.Susceptibility to oncogenic viruses in the dialysis patient has been linked to uremic immunodeficiency, which is characterized by an impaired function of monocytes with a T-cell activation defect resulting in reduced immunosurveillance.17Köhler H Girndt M Dumann H Klingel R The immune defect in kidney failure. I. Clinical manifestations. II. Mechanism of uremic immune defect.Dtsch Med Wochenschr. 1993; 118 (790-795): 757-761Google ScholarIs the enhanced cancer incidence of the dialysis patient more or less a reflection of a better surveillance?Regular dialysis therapy is an exceptional opportunity for early detection of malignancies. This is particularly true for cancer of the kidney, but also of the thyroid, which is frequently investigated in the diagnostic program of hyperparathyroidism. Therefore, excess elevation of SIR may be, at least in part, a consequence of better surveillance. But numerous convincing data show that uremia per se is an important promoting factor of malignancies.18Vamvakas S Bahner U Heidland A Cancer in end-stage renal disease: Potential factors involved.Am J Nephrol. 1998; 18: 89-95Google Scholar Thus, the morphology and genetics of kidney cancer in dialysis patients are different from renal cell cancer in the general population.9Chudek J Herbers J Wilhelm M Kenck C Bugert P Ritz E Waldman F Kovacs G The genetics of renal tumors in end-stage renal failure differs from those occurring in the general population.J Am Soc Nephrol. 1998; 9: 1045-1051Google Scholar In addition, data show significant changes in the DNA repair both before start of dialysis19Malachi T Zevin D Gafter U Chagnac A Slor H Levi J DNA repair and recovery of RNA synthesis in uremic patients.Kidney Int. 1993; 44: 385-389Google Scholar and after long-term renal replacement therapy.20Vamvakas S Bahner U Becker P Steinle A Götz R Heidland A Impairment of DNA repair in the course of long-term hemodialysis and under cyclosporine immunosuppression after renal transplantation.Transplant Proc. 1996; 28: 3468-3473Google Scholar In line with these studies, our group could recently demonstrate an increased damage in lymphocytes of patients before and after long-term hemodialysis therapy by assessing the number of micronuclei, which are cytoplasmic DNA-containing structures.21Stopper H Meysen T Böckenförde A Bahner U Heidland A Vamvakas S Increased genomic damage in lymphocytes of patients before and after long-term maintenance hemodialysis therapy.Am J Kidney Dis. 1999; 34: 1-5Abstract Full Text Full Text PDF Scopus (68) Google Scholar Interestingly, even in rats with moderate renal insufficiency, DNA damage of lymphocytes could be demonstrated.22Krivosiková Z Dusinská M Sebeková K Spustová V Heidland A Dzurik R The effect of losartan on DNA damage in the rat remnant kidney model.Neoplasm. 1999; (in press)Google Scholar In the 4/6 nephrectomized animals, incidence of single-strand breaks as evaluated by single-cell gel electrophoresis was markedly augmented.Why are malignancies enhanced in the younger dialysis populaton?The finding of cancer excess in the young dialysis patients (<35 years) is a new and surprising observation. Generally, a young healthy organism has better-functioning defense systems against DNA damage and cancer development compared with older persons. Most probably, they have a better capability to scavenge reactive oxygen species and, thus, a higher potential to prevent DNA damage. Moreover, even if DNA damage occurs, a young healthy organism will generally have better functioning repair systems to remove this damage and restore the original DNA structure. Finally, function of systems to detect and remove malignant cells from the organism, for example, via apoptosis, is better in young individuals. In contrast, in end-stage renal disease, these cancer defense mechanisms may be impaired because of the uremic state.Consequently, young patients with chronic renal failure will develop cancer with higher incidence compared with their healthy counterparts. Conversely, in advanced age, some cancer defense systems deteriorate, even in persons without renal impairment or other major disease. For example, mutations accumulate with age, and important tumor suppressor genes may be inactivated in advanced age, in both the presence and absence of renal disease. Hence, the difference in terms of cancer could vanish with advancing age. Conversely, the cancer risk of aging and uremia may be additive.There is another possible explanation for the “age phenomenon.” Renal impairment may have the same impact in terms of the induction of primary cancer lesions, for example, DNA mutations and malignant transformation of cells, both in younger and older patients. In this case, the increased detection of clinically manifest cancer may be because the stages of tumor promotion and progression have a faster course in younger patients.Another aspect concerns the viral-associated malignancies in the younger dialysis patients. It is conceivable that primary infections in the younger population are much more serious, if their immune system is impaired because of the uremic state. On the contrary, in the elderly, the consequences of immune dysfunction may be less severe for certain virus infections with regard to their antibody formation a long time ago.Is the lower relative prevalence of cancer in the elderly dialysis patient linked to the enhanced mortality?The most important factor for the age-dependent decline of SIR seems to be the reduced life expectancy in the elderly dialysis patient due to comorbid diseases, in particular from the cardiovascular system. The death rates recorded in Europe in nondiabetic patients aged 45 to 54 years were estimated to be 5 to 10 times greater than for similar cohorts of the general population in several European countries.23Brunner FP Selwood NM Profile of patients on RRT in Europe and death rates due to major causes of death groups.Kidney Int. 1992; 42: S4-S16Google Scholar According to the recent US Renal Data System Annual Data Report (1999),24Renal Data System US USRDS 1999 Annual Data Report. The National Institutes of Health, National Institute of Diabeties and Digestive and Kidney Diseases, Bethesda, MD1999Google Scholar the expected remaining lifetime for dialysis patients in the United States of the 30- to 34-year age group is about 9 years, and for the 65- to 69-year age group, only 3.2 years. Even in the pre–end-stage renal disease population, the expected remaining lifetime is markedly reduced. It averages about 15 years in the 30- to 40-year age group and 3.5 years in the 65- to 69-year age group. Thus, the age-dependent decline of the enhanced SIR in cancer of dialysis patients would result in all probability from both a smaller number of “new patients” for dialysis and a shorter exposure time (“long-standing cases”) to renal replacement therapy with less malignant cell transformation. With regard to these problems, data about the duration of dialysis treatment in the different age groups in the collaborative study would be of huge interest.Did the spectrum of cancer in the dialysis patient change within the last decades?In the 1970s and 1980s, numerous studies reported a marked increase of malignancies of the lung, stomach, prostate, colon, and corpus uteri, most likely a similar spectrum to that of the general non–end-stage renal disease population.2Port FK Ragheb NE Schwartz AG Hawthorne VM Neoplasms in dialysis patients: A population-based study.Am J Kidney Dis. 1989; 14: 119-123Google Scholar, 3Inamoto H Ozaki R Matsuzaki T Wakui M Saruta T Osawa A Incidence and mortality patterns of malignancy and factors affecting the risk of malignancy in dialysis patients.Nephron. 1991; 59: 611-617Google Scholar Because in the large collaborative study these cancers were not consistently elevated, we have to ask whether the spectrum of cancer changed in the past several years. Theoretically, cancer incidence could be reduced by numerous factors such as improved quality of dialysis therapy after better control of the uremic state (higher dose of dialysis, use of high-flux or more biocompatible membranes, as well as improved dialysate quality). Furthermore, correction of renal anemia with erythropoietin (instead of blood transfusions with the risk of transmissible diseases) may also diminish formation of oxygen radicals25Kristal B Shurtz-Swirski R Shasha SM Manaster J Shapiro G Furmanov M Hassan K Weissman I Sela S Interaction between erythropoietin and peripheral polymorphonuclear leukocytes in hemodialysis patients.Nephron. 1999; 81: 406-413Google Scholar and reduce the susceptibility to infections. Finally, administration of active vitamin D3 metabolites with better control of hyperparathyroidism, which has been linked to malignancies,26Kopple JD Massry SG Is there an association between neoplasia and primary or secondary hyperparathyroidism?.Am J Nephrol. 1988; 8: 437-448Google Scholar could be of importance in prevention of certain types of cancer.Potential role of smoking for the development of malignancies in the dialysis patientsIn the collaborative study, the potential role of smoking for cancer development was not investigated. Smoking is a major oxydative stress in addition to a source of mutagens.27Ames BN Shigenaga MK Hagen T Oxidants, antioxidants, and the degenerative diseases of aging.Proc Natl Acad Sci U S A. 1993; 90: 1915-1922Google Scholar In particular, for cancer of the kidney and the urinary tract, the pathogenetic role of smoking has been demonstrated. According to recent investigations, there exists a direct and significant dose-risk relationship for renal cell carcinoma and uroepithelial cell cancer.28Orth SR Ritz E Schrier RW The renal risks of smoking.Kidney Int. 1997; 51: 1669-1677Google Scholar Furthermore, in some virus-induced malignancies such as cancer of cervix uteri, nicotine has been assumed as a cocarcinogen. In end-stage renal disease, consequences of smoking may be aggravated by the accumulation of nicotine.29Perry RJ Griffiths W Dextraze P Solomon RJ Trebbin WM Elevated nicotine levels in patients undergoing hemodialysis: A role in cardiovascular mortality and morbidity?.Am J Med. 1984; 76: 241-246Google ScholarConsequences of high cancer incidence in dialysis patientsAs a result of this outstanding collaborative study, a meticulous monitoring of cancer should be performed, in particular in younger dialysis patients, although the value of screening of cancer in the dialysis population was a matter of controversy in the past. We should also keep in mind that in the elder dialysis patient, the absolute incidence of cancer is markedly enhanced. Therefore, screening of cancer in these patients should not be neglected. In particular in the absence of coexisting cardiovascular complications, life expectancy in dialysis is not so bad in the elderly. This month's discussion. . .The Journal Club focuses on an article entitled “Cancer in Patients on Dialysis for End-Stage Renal Disease: An International Collaborative Study” (Lancet 354:93-99, 1999) by Patrick Maisonneuve, Lawrence Agodoa, Ryszard Gellert, John H. Stewart, Gherardo Buccianti, Albert B. Lowenfels, Robert A. Wolfe, Elisabeth Jones, Alex P.S. Disney, Douglas Briggs, Margaret McCredie, and Peter Boyle. This month's discussion. . .The Journal Club focuses on an article entitled “Cancer in Patients on Dialysis for End-Stage Renal Disease: An International Collaborative Study” (Lancet 354:93-99, 1999) by Patrick Maisonneuve, Lawrence Agodoa, Ryszard Gellert, John H. Stewart, Gherardo Buccianti, Albert B. Lowenfels, Robert A. Wolfe, Elisabeth Jones, Alex P.S. Disney, Douglas Briggs, Margaret McCredie, and Peter Boyle. This month's discussion. . . The Journal Club focuses on an article entitled “Cancer in Patients on Dialysis for End-Stage Renal Disease: An International Collaborative Study” (Lancet 354:93-99, 1999) by Patrick Maisonneuve, Lawrence Agodoa, Ryszard Gellert, John H. Stewart, Gherardo Buccianti, Albert B. Lowenfels, Robert A. Wolfe, Elisabeth Jones, Alex P.S. Disney, Douglas Briggs, Margaret McCredie, and Peter Boyle. Recently, a large international collaborative study on cancer in patients on dialysis for end-stage renal disease was published by Patrick Maisonneuve and colleagues1Maisonneuve P Agodoa L Gellert R Stewart JH Buccianti G Lowenfels AB Wolfe RA Jones E Disney APS Briggs D McCredie M Boyle P Cancer in patients on dialysis for end-stage renal disease: An international collaborative study.Lancet. 1999; 354: 93-99Google Scholar in The Lancet (July 10, 1999). By use of dialysis registries from the United States, Europe, and Australia/New Zealand, a cohort of 831,804 patients in the period from 1980 to 1994 was assembled and the observed number of cancer matched with the respective background population. The raised overall risk of cancer in dialysis demonstrated in the collaborative study confirms and extends numerous earlier reports in smaller patient groups.2Port FK Ragheb NE Schwartz AG Hawthorne VM Neoplasms in dialysis patients: A population-based study.Am J Kidney Dis. 1989; 14: 119-123Google Scholar, 3Inamoto H Ozaki R Matsuzaki T Wakui M Saruta T Osawa A Incidence and mortality patterns of malignancy and factors affecting the risk of malignancy in dialysis patients.Nephron. 1991; 59: 611-617Google Scholar, 4Iseki K Osawa A Fukiyama K Evidence for increased cancer deaths in chronic dialysis patients.Am J Kidney Dis. 1993; 22: 308-313Google Scholar, 5Pope JC Koch MO Bluth RF Renal cell carcinoma in patients with end-stage renal disease: A comparison of clinical significance in patients receiving haemodialysis and those with renal transplants.Urology. 1994; 44: 497-501Google Scholar, 6Cuckovic C Djukanovic L Jankovic S Stanojcic A Dragicevic P Radmilovic A Lambic L Stojanovic M Milic M Bakovic J Radovic M Labudovic M Malignant tumors in hemodialysis patients.Nephron. 1996; 73: 710-712Google Scholar, 7Buccianti G Maisonneuve P Ravasi B Cresseri D Locatelli F Boyle P Cancer among patients on renal replacement therapy: A population-based survey in Lombardy, Italy.Int J Cancer. 1996; 66: 591-593Google Scholar It has to be stressed that inclusion of cancer patients of the predialysis period would have further increased the prevalence of cancer. Thus, in this study, a total of 47,866 patients (corresponding nearly to a twofold higher number of cancer patients in dialysis) with the previous diagnosis of cancer or those whose primary renal disease was attributed to malignancies or amyloidosis were excluded. There is evidence that the risk of cancer is already enhanced in pre–end-stage renal disease. Also in the collaborative study, the high incidence of malignancies within the first year of dialysis (as compared with the following years) underlines the importance of the predialysis period for the development of cancer, because most cancer types have latency periods of several years. The excessive overall incidence of cancer in the dialysis population of Australia/New Zealand is explained by the authors with a more accurate documentation in these countries, whereas registries of Europe and the United States may have been less complete. This is supported by the fact that in some European countries with a more precise documentation such as Sweden, Denmark, and The Netherlands, cancer prevalence in dialysis is comparable to that of Australia/New Zealand.1Maisonneuve P Agodoa L Gellert R Stewart JH Buccianti G Lowenfels AB Wolfe RA Jones E Disney APS Briggs D McCredie M Boyle P Cancer in patients on dialysis for end-stage renal disease: An international collaborative study.Lancet. 1999; 354: 93-99Google Scholar Enhanced cancer formation involved in particular the kidney and was positively related to the length of time on dialysis treatment and negatively to patients' age at the beginning of renal replacement therapy. Malignancies of the kidney were associated in high percentage with toxic nephropathy, but also with glomerulonephritis and arteriopathy. Several lines of evidence point to a causal relation between renal cell cancer and acquired renal cystic disease, which increases strikingly during long-term dialysis therapy.8Marple JT Mac Dougall M Chonko AM Renal cancer complicating acquired cystic kidney disease.J Am Soc Nephrol. 1994; 4: 1951-1956Google Scholar, 9Chudek J Herbers J Wilhelm M Kenck C Bugert P Ritz E Waldman F Kovacs G The genetics of renal tumors in end-stage renal failure differs from those occurring in the general population.J Am Soc Nephrol. 1998; 9: 1045-1051Google Scholar In its pathogenesis, the toxic effects of uremia are implicated, because after kidney transplantation, incidence of renal cysts and cancer is less frequent in the native kidneys.10Pecqueux JC Schwarz A Dieckmann KP Offermann G Cancer incidence in patients on chronic dialysis and in renal transplant recipients.Urol Int. 1990; 45: 290-292Google Scholar Analgesic abuse, the other contributor of renal cell carcinoma, has an especially high prevalence in Australia.1Maisonneuve P Agodoa L Gellert R Stewart JH Buccianti G Lowenfels AB Wolfe RA Jones E Disney APS Briggs D McCredie M Boyle P Cancer in patients on dialysis for end-stage renal disease: An international collaborative study.Lancet. 1999; 354: 93-99Google Scholar Furthermore, a high incidence of tumors of the bladder was observed associated with infectious, obstructive, and toxic nephropathies. The risk of bladder cancer was unrelated to duration of dialysis treatment. In end-stage renal disease, the slower transit of the urine with high content of toxic waste products could be involved in the pathogenesis of bladder cancer. A surprising observation is a high time-dependent increase of thyroid carcinoma in the dialysis patients. In the pathogenesis of thyroid cancer, enhanced formation of free radicals and an impaired scavenger system, in particular due to a decreased selenium level of the gland, is discussed.11Köhrle J Schmutzler C Fekete H Dreher I Goretzki P Simon D Gawlik D Behne D Brabant G The role of selenium in human thyroid carcinoma.Exp Clin Endocrinol. 1995; 103 (abstr): 117AGoogle Scholar It is conceivable that in uremia, the enhanced formation of reactive oxygen species in the presence of the frequently lowered plasma levels of the selenium and glutathione peroxidase12Bonomini M Albertazzi A Selenium in uremia.Artif Organs. 1995; 19: 413-448Google Scholar contribute to cancer development of the thyroid. Other types of enhanced cancer risk in the collaborative study were linked to infections with oncogenic viruses such as carcinoma of the tongue (human papilloma virus 16 [HPV-16]), cervix uteri (HPV-16 and HPV-18), and liver (hepatitis B and C virus infection). Also in Hodgkin's disease, the causal role of viral infection (Epstein-Barr virus [EBV]) is assumed. Recently, reactivation of EBV infection during long-term hemodialysis therapy has been described.13Winkelspecht B Müller-Lantzsch N Kohler H Serological evidence for reactivation of EBV infection due to uraemic immunodeficiency.Nephrol Dial Transplant. 1997; 12: 2099-2104Google Scholar Even in multiple myeloma there are hints for the involvement of virus infection. Thus, Kaposi's sarcoma–associated herpesvirus (KSHV) infection of bone marrow dendritic cells has been demonstrated in some myeloma patients.14Rettig MB Ma HJ Vescio RA Pöld M Schiller G Belson D Savage A Nishikubo C Wu C Fraser J Said JW Berenson JR Kaposi's sarcoma-associated herpesvirus infection of bone marrow dendritic cells from multiple myeloma patients.Science. 1997; 276: 1851-1854Google Scholar In the genome of KSHV, a homolog of human interleukin-6 (IL-6) could be identified.15Moore PS Boshoff C Weiss RA Chang Y Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV.Science. 1996; 274: 1739-1744Google Scholar It is interesting that IL-6, which is markedly enhanced in the plasma of dialysis patients, is a growth factor for myeloma cells due to both stimulation of cell growth and prevention of apoptosis.16Kishimoto T Akira S Taga T Interleukin-6 and its receptor: A paradigm for cytokines.Science. 1992; 258: 593-597Google Scholar However, it is unlikely that enhanced plasma levels of IL-6 in uremia play a causal role in the pathogenesis of myeloma with regard to its rare occurrence in end-stage renal failure. Susceptibility to oncogenic viruses in the dialysis patient has been linked to uremic immunodeficiency, which is characterized by an impaired function of monocytes with a T-cell activation defect resulting in reduced immunosurveillance.17Köhler H Girndt M Dumann H Klingel R The immun
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