Grantham 1j: Polycystic renal disease. In Earley LE, Gott- schalk CW (eds): Strauss and ... 4000 Leslie Street. Willowdale, Ontario M2K 2R9. (416) 493-7638.
I Editorials
Cancer and chronic renal failure George Digenis, MD Andreas Pierratos, MD, FRCPC Dimitrios G. Oreopoulos, MD, PhD, FRCPC, FACP
A Ithough several authors have asserted that cancer is more frequent in patients with uremia,1'2 no one has an explanation for the alleged association between cancer and renal failure. In this article we examine the relation between cancer and primary renal disease and between cancer and uremia.
who had different malignant diseases, 8 were found to have polycystic kidneys as a primary renal disease."3 However, a low incidence of tumours has been reported in reviews of the clinical course of polycystic kidney disease.14-16 Cancer and uremia
Cancer and primary renal disease
Analgesic nephropathy, Balkan nephropathy and polycystic kidney disease all have been linked to neoplasia. A number of researchers have reported an association between analgesic nephropathy and transitional-cell carcinoma of the urinary tract.3 6 In one study5 the possibility was raised of the carcinogenicity of phenacetin, which chemically resembles aniline, a known carcinogen. Balkan nephropathy is endemic to low-lying valleys of the Danube River basin. Interstitial nephritis develops in middle age, and dialysis is required after 2 or 3 years. No definite cause for the disease has been determined,7 but transitionalcell cancer develops in some of the patients. Sattler and colleagues8 have postulated unknown environmental factors that act as nephrotoxic and carcinogenic agents. The incidence of cancer in polycystic kidney disease remains to be determined, but many workers have reported renal-cell or transitional-cell carcinomas in one or both polycystic kidneys.9-12 Moreover, in a review of 35 patients with uremia Dr. Digenis is from the Division of Nephrology, Hippocratean Hospital, Athens, Dr. Pierratos is from the Division of Nephrology, Wellesley Hospital, Toronto, and Dr. Oreopoulos is from the Division of Nephrology, Toronto Westem Hospital.
Reprint requests to: Dr. Dimitrios G. Oreopoulos, Division of Nephrology, Toronto Westem Hospital, 399 Bathurst St., Toronto, Ont. M5T258 14
CMAJ, VOL. 135, JULY 1, 1986
In 1972 Penn and Starzll noted that malignant disease was found in 6 of 75 renal-transplant recipients within 4 months after transplantation. They suggested that patients with uremia may have an increased incidence of cancer. In 1977 Matas and associates2 found 13 tumours in a variety of organs in 896 patients undergoing dialysis at the University of Minnesota Hospitals. However, they acknowledged that because of their special interest in the association of cancer with uremia, their centre may have had higher rates of referral of such patients.17 Hurwich and coworkers18 and Tasker and collaborators19 reported single cases of malignant disease in patients with uremia. Miach and colleagues20 reported that 6 of 47 such patients had cancers but that the cancer had not directly caused their renal insufficiency. The patients underwent dialysis for an average of 12 months; two of the six had skin cancer. Sutherland and associates21 studied the causes of death in patients with chronic renal failure, excluding those with renal failure due to malignant disease and those who had been treated with immunosuppressive medications. Among 120 patients, malignant disease had developed in 4 within an average of 32.5 months from the onset of uremia. Lindner and coworkers22 also reported a high incidence of cancer in patients with uremia. Although most of these investigators did not mention whether a specific kind of tumour was predominant, some found an increased incidence of non-Hodgkin's lymphoma, a disease usually
seen in patients after transplantation.23 24
Multicentre studies After studying 834 patients with uremia in whom seven neoplasms were found, Bush and Gabriel25'26 concluded that uremia does not predispose to malignant disease. Similarly, Slifken and collaborators27 did not find an increased incidence of cancer in such patients. Kantor and colleagues24 studied almost 26 000 patients treated with dialysis and found that the overall relative risk of cancer was not significantly different from unity when compared with the national incidence. Data from the registry of the European Dialysis and Transplant Association (EDTA) have been the subject of several reports. In two studies Jacobs and associates analysed data from 168 dialysis centres28 and from 1086 centres in 30 countries.4 In both studies the incidence of cancer and the distribution of types were similar to those in the general population, although the age distributions were not necessarily similar. In the first study the age of the patients was more closely related to the cancer incidence than to the duration of renal failure. This study also showed a close relation between a history of analgesic nephropathy and cancer of the urinary tract. More recent analyses of data from the EDTA registry suggest that the same types of tumours develop in patients undergoing dialysis for uremia as in the general population, except that neoplasms of the urinary tract develop in those with analgesic nephropathy.2930 In view of this, Wing and coworkers31 concluded that large surveys did not confirm the high incidence of neoplasia in patients with uremia reported in the smaller studies. Recently, data collected before dialysis for 8452 patients with renal failure by the Australia and New Zealand registry showed an increased incidence of skin cancer, including melanomas.32 During dialysis the overall incidence of cancer was approximately twice that expected in the agematched general population. However, this increase was mainly due to cancers of the urinary tract associated with analgesic nephropathy, a frequent cause of renal failure in Australia and New Zealand. The differences among the various studies are probably due to several factors: there is a major difficulty in finding adequately matched controls; patients undergoing dialysis are highly selected, and the selection criteria vary from country to country; the size of the uremic population from which the sample is drawn is unknown; and reporting is incomplete, and the data are usually only for patients undergoing dialysis.
Pathogenesis Researchers who report a high incidence of
malignant disease in' patients with uremia have made various speculations about its pathogenesis. The two most important hypotheses are as follows. First, the uremic state is associated with immunodeficiency,33-37 which especially impairs cellular immunity, thus leading to an increased incidence of cancer.1338 Second, patients undergoing maintenance dialysis are exposed to a variety of environmental factors (e.g., substances in the water used for dialysis). Some authors have suggested that nitrates, nitrites, chloramines and other unknown trace elements may be carcinogens.38'39 This effect is increased in patients undergoing long-term dialysis, who are exposed to large volumes of dialysis fluid. If this theory is correct, geographic or even temporal variations40 in the composition of the water used in the dialysis solution might explain differences in cancer incidence. This hypothesis is supported by the differences in the incidence of renal osteodystrophy among various dialysis centres. Of course, this theory would not explain cancers that develop before dialysis is begun. Moreover, the types of neoplasms found in the uremic population are similar to those in the general population. This observation is evidence against the hypotheses that immunodeficiency or exposure to specific carcinogens causes specific malignant tumours to develop, as is the case after transplantation or analgesic abuse. Some studies have shown that the incidence of non-Hodgkin's lymphoma is significantly higher in patients with renal failure than in nonuremic controls.23,24 This observation is difficult to interpret because it is not known how many of these patients were previously treated with immunosuppressive drugs for their primary renal disease.41 Other questions No one has examined the risk of malignant disease in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). We are currently reviewing the data for patients undergoing CAPD in our program in an attempt to provide some answers to this question. Another question that requires study is whether the incidence of malignant disease in patients undergoing dialysis differs from that in patients with uremia who have not yet undergone dialysis. We may have to wait a long time for an answer to this question because of the difficulties inherent in the design and execution of a properly controlled study.
References 1. Penn I, Starzl TE: Malignant tumors arising de novo in immunosuppressed organ transplant recipients. Transplantation 1972; 14: 407-417 2. Matas AJ, Simmons RL, Kjellstrand CM et al: Increased
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incidence of malignancy in uremic patients and its significance to transplantation. Transplant Proc 1977; 9: 11371140 Hultengren N, Lagergren C, Ljungqvist A: Carcinoma of the renal pelvis in renal papillary necrosis. Acta Chir Scand 1965; 130: 314-320 Jacobs C, Brunner FP, Brynger H et al: Malignant diseases in patients treated by dialysis and transplantation in Europe. Transplant Proc 1981; 13: 729-732 Bengtsson U, Johansson S, Angerrall L: Malignancies of the urinary tract and their relation to analgesic abuse. Kidney Int 1978; 13: 107-113 Hoybye C, Nielsen OE: Renal pelvic carcinoma in phenacetin abusers. ScandJ Urol Nephrol 1971; 5: 190-192 Hall PW, Dammin GJ: Balkan nephropathy. Nephron 1978; 22: 281-285 Sattler TA, Dimitrov T, Hall PW: Relation between endemic (Balkan) nephropathy and urinary-tract tumours. Lancet 1977; 1: 278-280 Hayward WG: Hypernephroma in a polycystic kidney. J Urol 1946; 56: 190-192 Johnson WF: Carcinoma in polycystic kidney. J Urol 1953; 69: 10-12 Howard RM, Young JD: Two malignant tumors in a polycystic kidney. J Urol 1969; 102: 162-164 Roberts PF: Bilateral renal carcinoma associated with polycystic kidneys. Br Med J 1973; 3: 273-274 Kjellstrand CM: Are malignancies increased in uremia? Nephron 1979; 23: 159-161 Ward JN, Draper JW, Lavengood RW Jr: A clinical review of polycystic kidney disease in 53 patients. J Urol 1967; 98: 48-53 Grantham 1j: Polycystic renal disease. In Earley LE, Gottschalk CW (eds): Strauss and Welt's Diseases of the Kidney, 3rd ed, Little, Boston, 1979: 1123-1146 Simon HB, Thompson GJ: Congenital renal polycystic
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Computer Applications To Canadian Health
32.
CALL FOR PAPERS
33.
March 19 - 21, 1987 Toronto, Ontario
You are invited to submit a paper for presentation at 1CATCH '87, an exacting computerconferenceaimed at health care professionals from all fields and levelsof expertise. Your submission might be a descriptive paper, research paper, opinion, review or analytical paper. Subject areas will include: * Computer Education * Changing Professional Roles * Hospital Information Systems * Office Records and Information Retrieval * Technical advances to enhance the quality of health care * Cost Control, Ergonomics and Data Security This Conference will have four session tracks specifically for:
*Physicians * Nurses * Administrators * Allied Health Professionals Your paper must be submitted by Aust 1, 196 to allow for careful review by a committee of health care professionals. Draft manuscripts must betyped, double-spaced, and not exceed 2500 words. For furtherdetailed information and Submission Forms, please write or call: Mr. Donald Steen, CATCH '87 4000 Leslie Street Willowdale, Ontario M2K 2R9 (416) 493-7638 CA TCH'87is organized bythe College ofFamilyPhysicians ofCanada in conjunction width the Canadian MedicalAssociation, Canadian Nurses Association, Canadian Pharmaceutical Association, Medical Group ManagementAssociation ofCanada, andthe Royal College ofPhysicians & Surgeons of Canada.
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disease; clinical and therapeutic study of 366 cases. JAMA 1955; 159: 657-662 Matas AJ, Simmons RL, Kjellstrand CM et al: Increased incidence of malignancy during chronic renal failure. Lancet 1975; 1: 883-886 Hurwich BJ, Chait A, Dollberg M et al: Malignancy in chronic renal failure [C]. Lancet 1975; 2: 716 Tasker PR, Walden PA, Cower PE et al: Reticulosarcoma occurring during long-term hemodialysis. Clin Nephrol 1975; 3: 28-30 Miach PJ, Dawborn JK, Xipell J: Neoplasia in patients with chronic renal failure on long-term dialysis. Clin Nephrol 1976; 5:101-104 Sutherland GA, Glass J, Gabriel R: Increased incidence of malignancy in chronic renal failure. Nephron 1977; 18: 182-184 Lindner A, Farewell YT, Sherrard DJ: High incidence of neoplasia in uremic patients receiving long-term dialysis. Nephron 1981; 27: 292-296 Kinlen LJ, Eastwood JB, Kerr DN et al: Cancer in patients receiving dialysis. Br Med J 1980; 280: 1401-1403 Kantor A, Hoover R, Kinlen L et al: Cancer in patients receiving long-term dialysis treatment. Am J Epidemiol 1983; 118: 437-438 Bush A, Gabriel R: Cancer and patients with end-stage renal failure [C]. Br MedJ 1982; 284: 667 Idem: Cancer in uremic patients. Clin Nephrol 1984; 22: 77-81 Slifken RF, Goldberg J, Neff MS et al: Malignancy in end-stage renal disease. Trans Am Soc Artif Intern Organs 1977; 23: 34-38 Jacobs C, Reach I, Degoulet P: Cancer in patients on hemodialysis. N EnglJ Med 1979; 300: 1279-1280 Wing A, Broyer M, Brunner FP et al: Combined report on regular dialysis and transplantation in Europe, 13, 1982. Proc Eur Dial Transplant Assoc 1983; 20: 2-75 Idem: Talk manuscript and figures from combined report on regular dialysis and transplantation in Europe, 15, 1984. In Proceedings of the XXIInd Congress of the EDTA-ERA, Brussels, 1984: 30-36 Wing AJ, Jacobs C, Selwood NH: Cancer and patients with end-stage renal failure [C]. Br Med J 1982; 284: 504 Disney APS (ed): Eighth Report of the Australia and New Zealand Dialysis and Transplant Registry (ANZDA TA), Queen Elizabeth Hospital, Woodville, South Australia, 1985 Wilson WE, Kirkpatrick CH, Talmage DW: Suppression of immunologic responsiveness in uremia. Ann Intern Med 1965; 62: 1-14 Selroos 0, Pasternack A, Virolainen M: Skin test sensitivity and antigen-induced lymphocyte transformation in uraemia. Clin Exp Immunol 1973; 14: 365-370 Dobbelsein H: Immune system in uremia. Nephron 1976; 17: 409-414 Goldblum SE, Reed WP: Host defenses and immunologic alterations associated with chronic hemodialysis. Ann Intern Med 1980; 93: 597-613 Newburv WM, Sanford JP: Defective cellular immunity in renal failure: depression of reactivity of lymphocytes to phytohemagglutinin by renal failure serum. I Clin Invest 1971; 50: 1262-1266 Kjellstrand C, Matas A, Casio F et al: Are malignancies increased in uremia and dialysis? In Zurukzoglou W, Papadimitriou M, Pyrpasopoulos M et al (eds): Proceedings of the 8th International Congress on Nephrology, Athens, 1981, Karger, New York, 1981: 1217 Curtis JR: Cancer and patients with end-stage renal failure [E]. Br Med J 1982; 284: 69-70 Thysell H, Heinegard D, Lindholm T et al: Megalocystosis and chromosome aberrations in patients on regular hemodialysis. Clin Nephrol 1980; 13: 113-116 Kinlen L}, Sheil AG, Peto J et al: Collaborative United Kingdom-Australasian study of cancer in patients treated with immunosuppressive drugs. Br Med J 1979; 2: 1461 1466
