CancerCausesand Control,3, 323 -331
Risk factors for kidney cancer in New South Wales, Australia. II. Urologic disease, hypertension, obesity, and hormonal factors Margaret McCredie and
J. H. S t e w a r t
(Received 21January 1992;accepted in revisedforrn 24 March 1992) In a population-based case-control study of kidney cancer in New South Wales, Australia, data from structured interviews with 489 cases of renal cell cancer (RCC) and 147 cases of renal pelvic cancer (CARP) diagnosed in 1989 and 1990, and 523 controls from the electoral rolls, confirmed the link between obesity and RCC. In addition, regular consumption of'diet' pills independently increased the risk for this cancer. A diagnosis of hypertension at least two years before interview raised the risk for RCC, and regular use of 13-blockers,a class of antihypertensive drug, independently increased the risk for RCC and CaRP (risk ratio = 1.5-1.8). No independent effect was found for use of diuretics. Additional information provided by this study includes increased risks associated with kidney injury (RCC, CaRP)--possibly attributed to recall bias--and kidney infection (CARP), as well as a nonsignificantly raised risk linked with kidney stones (RCC, CARP) and a significantly reduced risk for RCC in persons giving a history of lower urinary tract infection. No significant association of RCC was found with hormonal factors (age at menarche or menopause; child-bearing; regular use of oral contraceptives or estrogens; hysterectomy or oophorectomy).
Key words:Australia, 13-blockers,case-control study, diuretics, hypertension, kidney cancer, obesity, populationbased, renal cell cancer, renal pelvic cancer, urologic disease. Introduction Various urologic conditions have been implicated in the etiology of cancer of the renal parenchyma (renal cell carcinoma, RCC) or cancer of the renal pelvis (CARP). However, the only associations proved statistically by epidemiologic study have been with kidney or bladder stones and kidney infection,1 kidney stones, 2 or urologic3 or genitourinary4 disease in general for RCC, and renal papillary necrosis s for CARP. Hypertension, x,4 antihypertensive drugs( and diuretics6,7 each have been linked with increased risk
for RCC, as have two diseases associated with high blood pressure--mycordial infarction8 and stroke. 1 Hypertension and antihypertensive medication (unspecified, but in most cases thought to include thiazide diuretics) increased the risk of RCC in a cohort study of Seventh-day Adventis& but, because of their high correlation, the independent effects of these factors could not be evaluated. As two major risk factors for CARP, smoking and consumption of phenacetincontaining analgesics, identified in New South Wales
Dr McCredie is with the NSW Central CancerRegistry and CancerEpidemiology Research Unit, NSW Cancer Council,Australia. Dr Stewart is with the Department of Renal Medicine, Westmead Hospital, Westmead, NSW, Australia. Address correspondence to Dr McCredie, Cancer Epidemiology Research Unit, NSW Cancer Council, PO Box 572, Kings CrossNSW 2011, Australia. The project was supported by tbe National Health and MedicalResearch CouncilofAustralia, the Government EmployeesAssistance to MedicalResearcb Fund, and the Australian Kidney Foundation. © 1992 Rapid Communications of Oxford Ltd
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M. McCredie and J. H. Stewart (Australia) 1°,"are both associated with accelerated atherogenesis, 12," one might expect an increased likelihood of coronary heart disease in patients with this cancer. That sex hormones may be implicated in RCC has been suggested by the following observations: (i) the incidence is about twice as common in men as in women; TM (ii) the production of this type of cancer has been found in male hamsters following long-term treatment with estrogens, 15 and the inhibition by an estrogen antagonist of transplanted estrogen-induced renal tumors in hamsters occurs; 16and (iii) admittedly slight clinical evidence. 17,~8However, there is no epidemiologic support for an association in humans with respect to use of estrogens, ~,4,6 age at menarche or menopause,6 or operations such as hysterectomy or oophorectomy? The association of RCC with diabetes 19 and thyroid disease2° implies endocrine influences other than those from sex hormones. Obesity has been identified as a risk factor for RCC, initially and more strongly in women, but recently also in men. 1,~-23 In view of a possible link of RCC with 'diet' pills, 7 and the demonstrated association between obesity and other estrogen-dependent tumors (e.g., breast24), the interrelationship of these factors, together with the roles of urologic disease, hypertension, and drugs used in the treatment of hypertension, have been examined in an international collaborative populationbased case-control study of RCC under the coordination of the United States National Cancer Institute. The main aims were to determine whether diuretic use was linked with RCC in a number of different populations, to confirm the risk associated with tobacco smoking, and to assess the role of antipyretic analgesics. The participating centers, either in areas of high incidence of RCC or with a particular interest in kidney cancer, were in the US (Minnesota), Denmark, Sweden, Germany (two centers), and Australia (New South Wales), with only the latter center including cases of renal pelvic cancer. Each study was designed to stand alone but identical protocols were used to permit subsequent pooled analysis. The analysis of results from New South Wales pertaining to urologic disease and hypertension are presented here.
Methods Potential cases were all incident cases in 1989-90 of cancer of the renal parenchyma (ICD-9 code 189.0; renal cell carcinoma; RCC) and renal pelvis (ICD-9 code 189.1; CARP) in residents of New South Wales (NSW) who were aged 20-79 years at diagnosis and who were on the electoral roll, were listed in the telephone directory, and could speak English. Control 324
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subjects were selected from the electoral rolls using proportional random sampling based on the expected age distribution of the cases; there was no matching by electoral district. Controls also had to be listed in the telephone directory and be able to speak English. Cases were identified through statutory notification to the NSW Central Cancer Registry by hospitals, pathology laboratories, and radiotherapy departments. 2sBecause delays in the routine notification process would have led to a greater loss of cases due to deteriorating health or death, monthly telephone calls were made to urologists throughout NSW for earlier ascertainment of cases. In the period up to 31 July 1991 (allowing for late notifications), 744 eligible cases of RCC and 200 of CaRP were identified. In the succeeding eight months, 24 additional cases were notified indicating that 97 percent of all cancers diagnosed within the study period were included in the case population. Permission for inclusion of an eligible case in the study was requested from the attending doctor, followed by a letter to the individual inviting participation. The release of information from the Cancer Registry was made conditional upon adherence to a strict protocol which did not permit repeated approaches to either the doctor or the patient, nor could information be obtained from relatives of the patients. For RCC, attrition due to death (23 percent), refusal (doctor, two percent; patient, one percent) or nonresponse (doctor, one percent; patient, five percent) resulted in a case group comprising 322 men and 181 women. For CARP, 59 men and 90 women were interviewed, death (15 percent), refusal by doctor (one percent), or patient (five percent), and nonresponse by doctor (three percent) or patient (two percent) accounting for the remainder. In each of the 12 fiveyear age groups between 20 and 79 years, the percentages of the potential RCC cases who participated were 80, 100, 83, 77, 79, 78, 75, 79, 74, 65, 55, and 47 respectively. For CARP, the percentage who participated in the nine five-year age groups between 35 and 79 years were 100, 100, 89, 89, 84, 90, 74, 58, and 59. The majority of the cases fell in the four highest five-year age groups. 26 The diagnosis of interviewed cases was based on histopathology of the kidney (87 percent RCC, 92 percent CARP) or other tissue (one percent RCC), fine-needle aspiration cytology of the kidney (four percent RCC), or by computerized tomography, ultrasound, or contrast radiography (eight percent of each cancer). Of the proportional random sample (n=1,090) obtained from the current electoral rolls for the state of NSW, telephone numbers were found for 803. An initial letter seeking participation in the study was fol-
Urologic disease and kidney cancer lowed, if necessary, by a second letter and up to 10 telephone calls. The information on the rolls was out of date for 60 subjects (52 moved, eight were dead) and 18 could not speak English. Of the remaining 725, 74 percent were interviewed, the remainder being comprised of refusals (ill health, seven percent; senility, less than one percent; other reasons, two percent; no reason, 16 percent) and nonrespondents (two percent). Among the controls, women who were not interviewed were slightly older than those who were (65 + 8 cf 62 + 9 years, t = 3.092, d.f. = 389, P < 0.001); no such difference was found for men. One trained interviewer carried out all the interviews between May 1989 and July 1991. She was not blind to case/control status but was required to adhere to the wording of the structured questionnaire so that it was not possible to probe cases to a greater degree than controls. Of the cases, all but 10 (seven RCC, three CARP) were interviewed within one year of diagnosis (55, 87, and 69 percent within three, six, and nine months of diagnosis, respectively). Personal interviews were held in the homes of all subjects who lived in the Sydney metropolitan area (256 RCC, 71 CARP, 232 controls). For subjects living in the remainder of NSW (233 RCC, 76 CARP, 291 controls), the checklists to be used in conjunction with the standard questionnaire were mailed with a request to keep them unopened but accessible for subsequent telephone interview. However, while all telephone respondents had kept the checklists at hand, about half had opened them before the interview took place. Self-administered questionnaires were completed by 14 RCC cases, two CaRP cases, and 12 controls as this was the only means by which these subjects would participate. The questionnaire sought information about the regular consumption of prescribed medicines such as diuretics, antihypertensive drugs, oral contraceptives, estrogens, and 'diet' pills; height (without shoes) and weight (usual weight throughout adult life); and a reproductive and medical history, in addition to data about other suspected risk factors and confounders. The type and/or brand of prescribed medicine (according to comprehensive checklists), the usual number taken per day, and the precise period of consumption were sought, explicitly excluding the period after 1 January 1987 for all subjects. Antihypertensive drugs (in this paper not including diuretics, which were analyzed separately) were classified according to their method of action as [3-blockers, a-blockers, vasodilators including calcium antagonists, angiotensin converting enzyme (ACE)-inhibitors, or 'other.' Similarly, diuretics were grouped as thiazide, loop, or 'other.' 'Diet' pills included amphetamines as well as appetite suppressants. Nonconsumers of prescribed
drugs were defined as those who had taken less than 'two tablets a week for two weeks or longer' before 1987. Subjects were asked if they had ever been told by a doctor that they had certain specified medical or surgical conditions and for the year of diagnosis. Only diagnoses before 1987 were used in the analyses and no validation of the information was performed.
Analysis Initial evaluation included inspection of frequencies of the variables. As the 28 self-administered questionnaires contained an unacceptably high level of missing data, it was decided to restrict the analysis to the 489 cases and 523 controls who were interviewed either face-to-face or by telephone. Tertiles of exposure variables were calculated on the basis of their distribution in the entire control group; tertiles for age were based on cases and controls combined. Body mass index (BMI) was calculated as usualweight/(height) 2for men and usual weight/(height) ~.s for women; 2' tertiles for BMI were derived for men and women separately. Relative risks (RR), together with 92 percent confidence intervals (CI), were estimated from multivariate logistic regression using EGRET 28according to Breslow and Day. 29All estimates of risk were adjusted for age (in tertiles), sex, and method of interview. The effect of each factor and of potential interactions was tested by the likelihood ratio test. Tests for trend were obtained by scoring the levels of the categorized exposure level, disregarding the nonexposed category and treating the scored variable as continuous. All factors with a statistically significant influence or for which there was prior evidence of an association were included in the final model which estimated the effect of each factor adjusted for all other significant factors.
Results Cases and controls are described in Table 1 with respect to the percentage (age-adjusted to the total population of subjects) in whom there had been a diagnosis, before 1987, of various medical and surgical conditions chosen because in previous studies they had been linked with kidney cancer. Table 2 gives similarly age-adjusted percentages of regular consumption of antihypertensive drugs, diuretics, potassium supplements, 'diet' pills, oral contraceptives, and estrogens. RRs (adjusted for age, sex, and method of interview) given in Tables 3 (for diagnoses), 4 (for drugs), and 5 (for obesity) show significantly increased risks associated with hypertension, potassium supplements, 'diet' pills, and obesity (RCC only); kidney infection (CARP only); kidney stones, kidney injury, antihypertensive drugs, and diuretics (both types of Cancer Causes and Control. Vol 3. 1992
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M. McCredie and J. H. Stewart T a b l e 1. Medical h i s t o r y ' - - p e r c e n t a g & of cases and controls, N e w S o u t h Wales, 198%90 Population controls
Hypertension Angina Heart attack Stroke Kidney stones Bladder stones Kidney infection Bladder infection Kidney injury Diabetes Thyroid disease
Renal cell cancer
Renal pelvic cancer
Males (n = 231)
Females (n = 292)
Males (n = 310)
Females (n = 179)
Males (n = 58)
Females (n = 89)
25.1 13.4 12.9 3.5 13.2 2.6 5.0 27.2 5.1 4.0 1.8
39.7 7.8 4.8 2.0 7.1 0.7 19.1 52.1 2.6 6.2 12.5
41.6 14.4 13.6 5.2 20.0 2.6 7.1 22.7 14.9 6.6 3.8
45.2 9.2 6.2 1.6 5.9 0 17.8 48.3 12.2 7.7 17.1
28.3 6.0 12.0 7.4 27.0 2.0 10.6 25.3 19.6 9.2 1.4
40.2 14.4 11.6 2.4 10.3 3.0 33.1 44.1 5.5 5.4 9.0
' Diagnosed before 1987. Age-adjusted to the total population of study subjects.
T a b l e 2. Regular c o n s u m p t i o n of prescribed medicines~---percentage b of cases and controls, N e w South Wales, 1989-90 Population controls
Antihypertensive drugs Diuretics Potassium supplements 'Diet' pills Oral contraceptives Estrogens
Renal cell cancer
Renal pelvic cancer
Males (n = 231)
Females (n = 292)
Males (n = 310)
Females (n = 179)
Males (n = 58)
Females (n = 89)
22.9 18.6 8.8 1.6
29.6 38.0 20.0 10.1 40.8 24.1
39.3 29.4 13.9 6.3 ---
44.0 47.0 26.4 15.8 31.3 15.9
26.3 13.1 5.7 4.8 ---
55.6 55.9 28.7 9.0 29.5 10.0
Taken before 1987. b Age-adjusted to the total population of study subjects.
T a b l e 3. Risk ratios (RR) • for k i d n e y cancer associated w i t h diseases diagnosed before 1987, N e w S o u t h Wales, 1989-90 i
Renal cell cancer
No. of
exposed controls Hypertension Angina Heart attack Stroke Kidney stones Bladder stones Kidney infection Bladder infection Kidney injury Diabetes Thyroid disease
178 56 45 14 49 8 66 219 20 26 38
' Adjusted for age, sex, method of interview. b CI = 95% confidence interval.
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Renal pelvic cancer
No. exposed
RR
(CI) b
No. exposed
RR
(CI) b
203 56 51 18 73 7 57 153 70 31 41
1.8 1.1 1.1 1.3 1.5 0.7 1.1 0.8 3.8 1.4 1.6
(1.3-2.3) (0.7-1.6) (0.7-1.7) (0.6-2.7) (1.0-2.2) (0.3-2.0) (0.8-1.7) (0.6-1.0) (2.3-6.4) (0.8-2.5) (1.0-2.6)
57 20 20 8 25 4 35 58 17 11 11
1.2 1.1 1.5 1.7 2.0 2.0 2.3 0.8 3.3 1.5 1.0
(0.8-1.8) (0.6-2.0) (0.9-2.7) (0.7-4.2) (1.2-3.5) (0.6-7.1) (1.4-3.8) (0.6-1.2) (1.7-6.7) (0.7-3.0) (0.5-2.0)
Urologic disease and kidney cancer Table 4. Risk ratios (RR)' for kidney cancer associated with prescribed medicines,New South Wales, 1989-90
Antihypertensive drugs Diuretics Potassium supplements 'Diet' pills
Renal pelvic cancer
Renal cell cancer
No. of exposed controls 143 156 78 32
No. exposed
RR
(CI) b
No. exposed
RR
(CI) b
191 171 87 50
2.0 1.7 1.5 2.1
(1.5-2.7) (1.2-2.2) (1.1-2.2) (1.3-3.5)
69 63 32 11
2.0 1.6 1.4 1.3
(1.4-3.0) (1.1-2.4) (0.9-2.3) (0.6-2.6)
a Adjusted for age, sex, method of interview. b CI = 95% confidence intervals.
Table 5. Risk of renal cell cancer associated with obesity, New South Wales, 1989-90 BMI c
Males No. of controls
74 Low 73 Medium 76 High Unknown 8 Test for trend a
No. of cases 88 78 141 3
Females RR a
(CI) b
1 1.0 (0.6-1.5) 1.6 (1.1-2.5) 0.3 (0.1-1.3) 5.55, P = 0.018
No. of controls
No. of cases
95 94 98 5
50 59 64 6
RR a
Males and females (CI) b
1 1.2 (0.8-2.0) 1.3 (0.8-2.1) 2.5 (0.7-8.8) 1.10, P = 0.294
No. of controls
No. of cases
169 167 174 13
138 137 205 9
RR'
(CI) b
1 1.1 (0.8-1.5) 1.5 (1.1-2.0) 0.9 (0.4-2.2) 6.05, P = 0.014
RR = risk ratio model adjusted for age, sex, method of interview. b CI = 95% confidence interval. c BMI, body mass index, calculated as usual weight/height2 for men and usual weight/height *,5for women; tertiles were 25.34 for men and 30.79 for women. d X2 excludes unknown category.
cancer). A history of bladder infection was related to a reduced risk of RCC. However, when further adjustment was made in the logistic regression model for each of these factors and for cigarette smoking, and obesity (RCC) or phenacetin-containing analgesics (CARP), many of the risk estimates lost their statistical significance (Table 6).
Diuretics When adjusted for antihypertensive drugs (as well as age, sex, method of interview, smoking, and obesity [RCC] or phenacetin consumption [CARP]), diuretics (all types considered together) no longer increased the risk for RCC (RR= 1.2, CI=0.9-1.7) or CaRP (RR --- 1.2, CI = 0.8-1.9). When the analysis for RCC was restricted to women in whom no diagnosis of hypertension had been made prior to 1987 and who had not taken antihypertensive drugs, no increased risk was found for women of any age (RR = 1.2, CI = 0.71.9) or for those aged less than 59 years (the lowest terfile; RR = 1.6, CI = 0.7-3.6). Of subjects who had ever taken diuretics, the majority also had taken antihypertensive drugs at some time (controls, 55 percent; RCC, 73 percent; CARP, 79 per-
cent). Similarly, most subjects who ever took antihypertensive drugs, also had taken diuretics (controls, 60 percent; RCC, 65 percent; CARP, 75 percent). Separate analyses were carried out for diuretic use among those who had, and those who had not, taken antihypertensive drugs, and also among those who had, and those who had not, reported hypertension. In none of these groups did diuretic use significantly increase the risk of RCC or CARP. Compared with those who had never used diuretics regularly, no trend was found in risk for RCC with the number of years before diagnosis that diuretics were first taken, the risk estimates being 0.8 (CI = 0.4-1.2), 1.2 (CI = 0.8-1.9) and 1.3 (CI = 0.8-2.2) for 1-8, 9-15 and 16 or more years, respectively. For neither type of cancer was there any association with thiazide, loop, or 'other' diuretics, once adjustment had been made for the effect of antihypertensive drugs. Potassium supplements, which were almost invariably taken with diuretics, did not independently alter the risk for RCC or CARP. The reason given for taking diuretics was 'to lose weight' by only two percent of each group of subjects; 'to lower blood pressure' by 53 percent (RCC), 42 perCancer Causes and Control. Vol 3. 1992
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M. McCredie and J. H. Stewart Table 6. Mutually adjusted risk factors* for kidney cancer, New South Wales 1989-90
Table 7. Risk of renal cell cancer associated with hypertension, New South Wales, 1989-90
Renal cell cancer
No. of exposed
Hypertension D-blockers Kidney stones Kidney infection Bladder infection Kidney injury Thyroid disease 'Diet' pills
RR b
(CI) o
1.6 1.5 1.5 0.9 0.7 3.6 1.5 2.1
(1.1-2.2) (1.0-2.3) (1.0-2.3) (0.6-1.4) (0.5-0.9) (2.1-6.2) (0.%2.6) (1.2-3.5)
Renal pelvic cancer RR d
(CI) c
2.0 1.3 1.7
(1.2-3.4) (0.7-2.4) (1.0-3.1)
3.3
(1.5-7.4)
"Also adjusted for age, sex, method of interview, and cigarette smoking. b RR = risk ratio adjusted for (a) and body mass index. ° CI = 95% confidence interval. d R R = r i s k ratio adjusted for (a) and phenacetin-containing analgesics. ' Not included in final model as no a priori link with CaRP and no association demonstrated in preliminary analyses.
Hypertension Never diagnosed A 1980-86 A 1970-79 A 1940-69
Controls Cases 344 79 48 51
268 86 50 67
RR'
(CI) b
1 1.5 1.4 1.8
(1.0-2.3) (0.9-2.3) (1.1-2.9)
' RR = risk ratio, model adjusted for age, sex, method of interview, body mass index, smoking, p-blockers, bladder infections, kidney injury, and 'diet pills'. b CI = 95% confidence intervals. A = diagnosis.
For neither RCC nor CaRP did the risk rise significantly with increasing years of consumption of [3-blockers.
Hypertension cent (CARP), and 46 percent (controls); 'for heart disease' by five percent, zero and three percent; and 'to reduce swelling' by 38 percent, 53 percent, and 48 percent, respectively; other reasons comprised the remainder.
Antihypertensive drugs Regular consumption of antihypertensive drugs (all types considered together) remained a significant risk factor for RCC when, in addition to age, sex, method of interview, smoking, and obesity, terms for diuretics and potassium supplements were included in the model (RR = 2.0, CI = 1.4-2.7) and when the presence of hypertension was taken into account (RR--1.5, CI = 1.0-2.2). When B-blockers, oL-blockers, vasodilators, ACE-inhibitors, and 'other' antihypertensive drugs were entered simultaneously into a logistic regression model (adjusted for age, sex, method of interview, obesity, and smoking), 13- and o~-blockers significantly increased the risk for RCC (RR = 1.8, CI = 1.3-2.6; and RR = 1.6, CI = 1.1-2.4, respectively). However, in a full model containing terms for hypertension and all other significant risk factors, only [3-blockers increased the risk (RR = 1.5, CI = 1.0-2.3), and this seemed to occur in women (RR= 1.8, CI=1.0-3.2) rather than in men (RR=I.3, CI = 0.7-2.3). Similarly, in a model containing terms for all significant risk factors for CARP, it was regular consumption of f3-blockers rather than other antihypertensive drugs that increased the risk (RR = 1.8, CI = 1.1-2.9), and again the effect was seen in women (RR=3.2, CI = 1.7-6.2) but not men (RR = 0.8, CI = 0.3-2.1). 328
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The estimate of risk for RCC associated with a diagnosis of hypertension before 1987 was reduced but remained significant after adjustment for B-blockers and all other risk factors (RR = 1.6, CI = 1.1-2.2; Table 6), the effect being apparent in men (RR=2.3, CI = 1 . 4 - 3 . 6 ) rather than women (RR = 1.2, CI = 0.71.9). When duration of hypertension was grouped into tertiles, although no clear 'dose-response' was seen, there was an increased risk in each category and those whose hypertension had been diagnosed for more than 20 years had the highest risk (RR = 1.8, CI = 1.1-2.9; Table 7).
Urologic disease Injury to the kidney showed a threefold increased risk of each type of kidney cancer (Table 6). Lower urinary tract infections appeared to decrease the risk of RCC (RR = 0.7, CI = 0.5-0.9). Once the effect of other risk factors had been taken into account, the association with kidney stones was stronger in men (RR = 1.8, C I = 1.1-3.0 for RCC; RR=2.0, CI=0.9-4.6 for CARP) than in women (RR = 0.9, CI---0.4-2.2 for RCC; RR = 1.1, CI = 0.4-3.2 for CARP). However, it was in women rather than men that there was some association of kidney infection with CaRP (RR = 1.9, CI=0.9-3.8 in women; RR=0.9, CI=0.2-3.2 in men).
Other diseases related to hypertension Neither angina, heart attack, nor stroke significantly increased the risk for RCC, the point estimates being 1.1,1.1, and 1.3, respectively. Nor was an association of these diseases found with CARP, although the esti-
Urologic disease and kidney cancer mates of risk were somewhat higher for heart attack (RR=I.6, CI=0.9-2.8) and stroke (RR=I.6, CI = 0.6-4.1) than for angina (RR = 1.0).
Obesity Compared with subjects in the lowest tertile of body mass index (BMI), there was a rising risk of RCC with increasing measure of obesity (Table 5). The highest risk was seen in the upper tertiles of BMI both for men and for women when considered separately. 'Diet' pills (when adjusted for all other significant factors, including obesity) increased the risk for RCC (RR = 2.0, CI--1.2-3.4), the risk in men (RR = 2.5, CI = 0.8-7.8) appearing to be higher than in women (RR -- 1.5, CI = 0.8-2.7). No link with obesity or 'diet' pills was found for CARP.
Hormonal factors Several endocrine-related factors were examined in women in relation to the risk for RCC. Neither age at menarche nor age at natural menopause was associated with this cancer. Having a hysterectomy increased the risk of RCC (RR = 1.8, CI--1.2-2.7) but bilateral oophorectomy did not (RR=I.4, CI=0.8-2.4). Neither age at hysterectomy nor age at oophorectomy showed a trend in risk. Nonsignificant associations ( P = 0.10) with RCC were found for regular use of oral contraceptives (RR = 0.7, CI = 0.4-1.1) and regular use of estrogens (RR = 1.4, CI = 0.9-2.1) but, for each type of drug, no gradation in risk was seen when terms for 'age at startrag' and 'duration of use' were incorporated simultaneously in a logistic model. Having borne at least one child reduced the risk of RCC (RR = 0.6, CI = 0.3-1.1) but when the effects of 'age at first child' and 'number of children' were examined together, no trends in risk were found. Adjustment for obesity, cigarette smoking, and the hormonal factors resulted in the risk for RCC associated with each of these hormonal variables becoming less significant.
Thyroid disease and diabetes No link with diabetes was found for either type of kidney cancer. Thyroid disease was not related to CARP, and adjustment for all significant risk factors lessened its apparent association with RCC (RR--1.5, CI = 0.9-2.6).
Discussion o f the conditions examined here, only kidney injury (for both types of kidney cancer), kidney infection (for
CaRP only), and hypertension (for RCC only) appeared to increase the risk for renal cancer, the other associations losing their statistical significance when the effects of possible confounding factors were taken into account. While the RRs associated with kidney injury are relatively high (about three for each cancer), this is a situation in which recall bias is likely, and the finding, as in previously published studies, 1,4,9must be regarded as provisional. A history of kidney infection may be merely a marker for the presence of another precancerous condition, the most likely candidate being renal papillary necrosis, which frequently manifests only as a tendency to pyelonephritis and, in Australia, is much more common in women (in whom an association with infection was found in this study) than men. That the link between RCC and high blood pressure was increased by the duration of recognized hypertension strengthens the likelihood that this condition contributes directly or indirectly to the causation of RCC, rather than appearing as a result of the kidney tumor. The definition used for this study, 'hypertension diagnosed by a doctor as reported by the subject,' is used frequently and has been validated in the US 3°but not in Australia. The extent to which the risk of RCC posed by hypertension was not from the disease itself, but from its treatment, was addressed in the multivariate analysis. Subjects diagnosed with hypertension during 1940-69 had the greatest risk of RCC (Table 6) but the suggestion that thiazide diuretics might be responsible was not supported. These diuretics were introduced in NSW only in the late 1950s, their major use for the treatment of hypertension being in the 1970s. During most of the past two decades, J3-blockers and diuretics, separately or combined, have been the most frequently prescribed drugs for high blood pressure. Unlike previous studies,6,7 here diuretics did not independently increase the risk for kidney cancer, either when used as a treatment for hypertension, or when taken by women who did not have hypertension. The initial report of a link between diuretic use and RCC was in women under the age of 55 years; we could find no association in general, in women, or in our lowest age group (under 59 years). Only two percent of subjects reported taking diuretics specifically to lose weight. In both forms of kidney cancer, the case for an etiologic role for [~-blockers independently of hypertension is weakened by the association being found predominantly in women. Duration of exposure was not related to risk, but no measure of intensity of exposure could be applied because of variation in the dose taken by individual patients, and the many different J3-blockers used. About 20 percent of controls Cancer Causes and Control. Vol 3. 1992
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M. McCredie and J. H. Stewart and 10 percent of cases who took 13-blockers did not have hypertension; coronary heart disease is the other common reason for taking these drugs. Neither of the common extra-renal diseases associated with hypertension, coronary heart disease (recorded here as angina or heart attack), or stroke, showed a positive relationship to either form of kidney cancer. Women with CaRP did have a history of angina or heart attack about twice as frequently as female controls or cases of RCC, but this could not be attributed, contrary to what might have been expected, to a link with smoking or analgesic abuse. Diseases of the bladder were not associated with an increased risk of either form of kidney cancer; in fact, the risk was reduced in those giving a history of bladder infection. As it is difficult to envisage a protective role of bladder infection itself, one must consider the possibility that cystitis is more likely to occur in people who, for unrelated reasons, have a reduced likelihood of kidney cancer. Both obesity and regular use of 'diet' pills were confirmed as risk factors for RCC but, in this study, no links could be found with either diabetes or thyroid disease. 'Diet' pills were taken for mental stimulation, rather than for reducing weight, only by a minority of subjects. Regarding factors related to female reproductive history, a pattern emerged of a decreased risk associated with use of oral contraceptives or having borne children, and an increased risk with taking estrogens, or having had either hysterectomy or bilateral oophorectomy. However, none of these relationships was significant in the multivariate analysis. No casecontrol study has examined the link between oral contraceptives and RCC, but three cohort investigations also failed to find an association. 31 Selection bias in this study must be considered because of nonparticipation among cases due to illness or death (23 percent RCC; 15 percent CARP) and of nonresponse among the controls (26 percent). Cases and female controls who were not interviewed were slightly older than those who were interviewed. Apart from these observations, we could not determine the extent to which bias was introduced as we had no measure of social class (apart from unsatisfactory groupings based on postcode of residence) and no access to medical records. Detailed analysis of selection bias in another study of RCC 32found higher socioeconomic class and a history of renal stones to be predictors of participation by both cases and controls; obesity in women, hypertension, and nonsmoking to be predictors in cases only; and heart disease to be associated with control participation and case nonparticipation. Thus, doubts were cast on the risk estimates for obesity in women and hypertension; it is conceivable that simi330
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lar bias could negate the findings from the current study with respect to these factors. The NSW electoral rolls, as a source of populationbased controls, have the drawback that they are updated only every six months to three years depending on the area in which an election is to be held. Electoral enrolment is compulsory for all persons over the age of 18 years who were born in, or who have become permanent residents of, Australia; thus people not on the electoral roll are, for the most part, recent immigrants and transient residents, some of whom would not be fluent in English. In NSW, 97 percent of households have the telephone connected. Although the telephone company will not release any details about 'unlisted' telephone numbers, seven to 12 percent of telephones in NSW, depending on the area, are not listed in the directories? Greater proportions of 'unlisted' telephones are in urban than rural areas, and in suburbs of higher socioeconomic class. Separate analysis of face-to-face and of telephone interviews identified no systematic bias with respect to use of prescribed medicines or self-reported medical conditions despite the fact that about half of the telephone respondents had seen the checklist of drugs before the interview began? 4 However, it is possible that there was differential reporting between cases and controls. Because hypertension is so common among middleaged people in Western societies, the population attributable risk (16 percent) is second only to that for smoking as an etiologic factor for RCC. 1," Obesity, which is also a common problem of modern society, is associated with the same magnitude of risk for RCC; the population attributable risk for our definition of obesity (the highest tertile) was 13 percent. While the associations between these two conditions and RCC may be indirect, relating to lifestyle exposures such as diet and exercise or to an inherited predisposition, the links with hypertension and obesity may explain why the incidence of cancer of the kidney is increasing faster than almost any other malignancy.36,37 Acknowledgements--We are grateful to Professor D. Raghavan, now at Roswell Park Cancer Institute, Buffalo, NY (US) for his participation in the design of this study; to the urologists of New South Wales for permission to include their patients in this study; to Joy Gillies for conducting the interviews with all the cases and controls; and to Lesley Porter for coding the questionnaires and all data entry.
References 1. McLaughlin JK, Mandel JS, Blot WJ, Schuman LM,
Urologic disease and kidney cancer Mehl ES, Fraumeni JF Jr. A population-based case-control study of renal cell carcinoma.JNC11984; 72: 275-84. 2. Talamini R, Bar6n AE, Barra S, et al. A case-control study of risk factor for renal cell cancer in northern Italy. Cancer Causes Control 1990; 1: 125-31. 3. McCredie M, Ford JM, Stewart JH. Risk factors for cancer of the renal parenchyma. IntJ Cancer 1988; 42:13-6. 4. Asal NR, Geyer JR, Risser DR, Lee ET, Kadamani S, Cherng N. Risk factors in renal cell carcinoma. II. Medical history, occupation, multivariate analysis, and conclusions. Cancer Det Prey 1988; 13: 263-79. 5. McCredie M, Stewart JH, Carter JJ, Turner J, Mahony JF. Phenacetin and renal papillary necrosis: Independent risk factors for renal pelvic cancer. Kidney Int 1986; 30" 81-4. 6. Yu MC, Mack TM, Hanisch R, Cicioni C, Henderson BE. Cigarette smoking, obesity, diuretic use, and coffee consumption as risk factors for renal cell carcinoma. JNC11986; 77: 351-6. 7. McLaughlin JK, Blot WJ, Fraumeni JF Jr. Diuretics and renal cell cancer.JNCI 1988; 80: 378. 8. Wynder EL, Mabuchi K, Whitmore WF Jr. Epidemiology of adenocarcinoma of the kidney.JNC11974; 53: 1619-34. 9. Fraser GE, Phillips RL, Beeson WL. Hypertension, antihypertensive medication and risk of renal carcinoma in California Seventh-day Adventists. Int J Epidemiol 1990; 19: 832-8. 10. McCredie M, Stewart JH, Ford JM, MacLennan RA. Phenacetin-containing analgesics and cancer of the bladder or renal pelvis in women. BrJ Uro11983; 55: 220-4. 11. McCredie M, Stewart JH, Ford JM. Analgesics and tobacco as risk factors for cancer of the ureter and renal pelvis.J Uro11983; 130: 28-30. 12. Nanra RS, Stuart-Taylor J, de Leon AH, White KH. Analgesic nephropathy: etiology, clinical syndrome, and clinicopathological correlations in Australia. Kidney Int 1978; 13: 79-92. 13. Dubach UC, Rosner B, Stiirmer T. Epidemiologic study of analgesic abuse: Mortality study in 7275 working women (1968-87). Kidney Int 1991; 40: 728-33. 14. Muir C, Waterhouse J, Mack T, Powell J, Whelan S, eds. Cancer Incidence in Five Continents. Vol. V. Lyon, France: International Agency for Research on Cancer, 1987; IARC Sci. Pub. No. 88. 15. Bloom HJG, Roe FJC, Mitchley BCV. Sex hormones and renal neoplasia. Cancer 1967; 20:2118-24. 16. Sufrin G. Spontaneous, hormonal and chemically induced animal models of renal adenocarcinoma. In: Sufrin G, Becldey SA, eds. Renal Adenocarcinoma. Geneva: UICC, 1980. 17. Bellet RE, Squitieri AP. Estrogen-induced hypernephroma.J Uro11974; 112: 160-1. 18. Nissenkorn I, Servadio C, Avidor I. Oestrogen-induced renal carcinoma. BrJ Uro11979; 51: 6-9. 19. Kantor AF. Current concepts in the epidemiology and etiology of primary renal cell carcinoma. J Urol 1977;
117: 415-7. 20. Tucker MA, Boice JD, Hoffman DA. Second cancer following cutaneous melanoma and cancers of the brain, thyroid, connective tissue, bone, and eye in Connecticut, 1935-82. NCI Monogr 1985; 68: 161-89. 21. Maclure KM, MacMahon B. A case-control study of renal adenocarcinoma (Abstract). Am J Epidemio11985; 122: 520. 22. Goodman MT, Morgenstern H, Wynder EL. A casecontrol study of factors affecting the development of renal cell cancer. AmJ Epidemio11986; 124: 926-41. 23. Asal NR, Risser DR, Kadamani S, Geyer JR, Lee ET, Cherng N. Risk factors in renal cell carcinoma: 1. Methodology, demographics, tobacco, beverage use, and obesity. Cancer Det Prey 1988; 11: 359-77. 24. De Waard F, Trichopoulos D. A unifying concept of the aetiology of breast cancer. IntJ Cancer 1988; 41: 666-9. 25. McCredie M, Coates M, Churches T, Taylor R. Cancer incidence in New South Wales, Australia. EurJ Cancer 1991; 27: 928-31. 26. McCredie M, Stewart JH. Risk factors for kidney cancer in New South Wales: IV. Occupation. Br J Ind Med (submitted). 27. Micozzi MS, Albanes D, Jones DY, Chumlea WC. Correlations of body mass indices with weight, stature, and body composition in men and women in NHANES I and II. AmJ Clin Nutr 1986; 44: 725-31. 28. Statistics and Epidemiology Research Corporation. EGRET. Seattle, WA: Statistics and Epidemiology Research Corporation, 1990. 29. Breslow NE, Day NE. Statistical Methods in Cancer Research. Vol L The Analysis of Case-control Studies. Lyon, France: International Agency for Research on Cancer, 1980; IARC Sci. Pub. No. 32. 30. Paffenbarger RS, Wing AL, Hyde RT, Jung DL. Physical activity and incidence of hypertension in college alumni. AmJ Epidemio11983; 117: 245-57. 31. Milne R, Vessey M. The association of oral contraception with kidney cancer, colon cancer, gallbladder cancer (including extrahepatic bile duct cancer) and pituitary tumours. Contraception 1991; 43: 667-93. 32. Maclure KM, Hankinson S. Analysis of selection bias in a case-control study of renal adenocarcinoma. Epidemiology 1990; 1: 441-7. 33. Telecom Directory Services. Silent Line Report--DASComputerised. Melbourne, Australia: Telecom, March 1992. 34. McCredie, Stewart JH. In preparation, 1992. 35. McCredie M, Stewart JH. Risk factors for kidney cancer in New South Wales: I. Cigarette smoking. EurJ Cancer 1992 (in press). 36. McCredie M, Coates MS, Ford JM. The changing incidence of cancer in adults in New South Wales. IntJ Cancer 1988; 42: 667-71. 37. Devesa SS, Silverman DT, Young JL, et al. Cancer incidence and mortality trends among whites in the United States.JNCI 1987; 79: 701-70.
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Risk factors for kidney cancer in New South Wales, Australia. II. Urologic disease, hypertension, obesity, and hormonal factors Margaret McCredie and
J. H. S t e w a r t
(Received 21January 1992;accepted in revisedforrn 24 March 1992) In a population-based case-control study of kidney cancer in New South Wales, Australia, data from structured interviews with 489 cases of renal cell cancer (RCC) and 147 cases of renal pelvic cancer (CARP) diagnosed in 1989 and 1990, and 523 controls from the electoral rolls, confirmed the link between obesity and RCC. In addition, regular consumption of'diet' pills independently increased the risk for this cancer. A diagnosis of hypertension at least two years before interview raised the risk for RCC, and regular use of 13-blockers,a class of antihypertensive drug, independently increased the risk for RCC and CaRP (risk ratio = 1.5-1.8). No independent effect was found for use of diuretics. Additional information provided by this study includes increased risks associated with kidney injury (RCC, CaRP)--possibly attributed to recall bias--and kidney infection (CARP), as well as a nonsignificantly raised risk linked with kidney stones (RCC, CARP) and a significantly reduced risk for RCC in persons giving a history of lower urinary tract infection. No significant association of RCC was found with hormonal factors (age at menarche or menopause; child-bearing; regular use of oral contraceptives or estrogens; hysterectomy or oophorectomy).
Key words:Australia, 13-blockers,case-control study, diuretics, hypertension, kidney cancer, obesity, populationbased, renal cell cancer, renal pelvic cancer, urologic disease. Introduction Various urologic conditions have been implicated in the etiology of cancer of the renal parenchyma (renal cell carcinoma, RCC) or cancer of the renal pelvis (CARP). However, the only associations proved statistically by epidemiologic study have been with kidney or bladder stones and kidney infection,1 kidney stones, 2 or urologic3 or genitourinary4 disease in general for RCC, and renal papillary necrosis s for CARP. Hypertension, x,4 antihypertensive drugs( and diuretics6,7 each have been linked with increased risk
for RCC, as have two diseases associated with high blood pressure--mycordial infarction8 and stroke. 1 Hypertension and antihypertensive medication (unspecified, but in most cases thought to include thiazide diuretics) increased the risk of RCC in a cohort study of Seventh-day Adventis& but, because of their high correlation, the independent effects of these factors could not be evaluated. As two major risk factors for CARP, smoking and consumption of phenacetincontaining analgesics, identified in New South Wales
Dr McCredie is with the NSW Central CancerRegistry and CancerEpidemiology Research Unit, NSW Cancer Council,Australia. Dr Stewart is with the Department of Renal Medicine, Westmead Hospital, Westmead, NSW, Australia. Address correspondence to Dr McCredie, Cancer Epidemiology Research Unit, NSW Cancer Council, PO Box 572, Kings CrossNSW 2011, Australia. The project was supported by tbe National Health and MedicalResearch CouncilofAustralia, the Government EmployeesAssistance to MedicalResearcb Fund, and the Australian Kidney Foundation. © 1992 Rapid Communications of Oxford Ltd
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M. McCredie and J. H. Stewart (Australia) 1°,"are both associated with accelerated atherogenesis, 12," one might expect an increased likelihood of coronary heart disease in patients with this cancer. That sex hormones may be implicated in RCC has been suggested by the following observations: (i) the incidence is about twice as common in men as in women; TM (ii) the production of this type of cancer has been found in male hamsters following long-term treatment with estrogens, 15 and the inhibition by an estrogen antagonist of transplanted estrogen-induced renal tumors in hamsters occurs; 16and (iii) admittedly slight clinical evidence. 17,~8However, there is no epidemiologic support for an association in humans with respect to use of estrogens, ~,4,6 age at menarche or menopause,6 or operations such as hysterectomy or oophorectomy? The association of RCC with diabetes 19 and thyroid disease2° implies endocrine influences other than those from sex hormones. Obesity has been identified as a risk factor for RCC, initially and more strongly in women, but recently also in men. 1,~-23 In view of a possible link of RCC with 'diet' pills, 7 and the demonstrated association between obesity and other estrogen-dependent tumors (e.g., breast24), the interrelationship of these factors, together with the roles of urologic disease, hypertension, and drugs used in the treatment of hypertension, have been examined in an international collaborative populationbased case-control study of RCC under the coordination of the United States National Cancer Institute. The main aims were to determine whether diuretic use was linked with RCC in a number of different populations, to confirm the risk associated with tobacco smoking, and to assess the role of antipyretic analgesics. The participating centers, either in areas of high incidence of RCC or with a particular interest in kidney cancer, were in the US (Minnesota), Denmark, Sweden, Germany (two centers), and Australia (New South Wales), with only the latter center including cases of renal pelvic cancer. Each study was designed to stand alone but identical protocols were used to permit subsequent pooled analysis. The analysis of results from New South Wales pertaining to urologic disease and hypertension are presented here.
Methods Potential cases were all incident cases in 1989-90 of cancer of the renal parenchyma (ICD-9 code 189.0; renal cell carcinoma; RCC) and renal pelvis (ICD-9 code 189.1; CARP) in residents of New South Wales (NSW) who were aged 20-79 years at diagnosis and who were on the electoral roll, were listed in the telephone directory, and could speak English. Control 324
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subjects were selected from the electoral rolls using proportional random sampling based on the expected age distribution of the cases; there was no matching by electoral district. Controls also had to be listed in the telephone directory and be able to speak English. Cases were identified through statutory notification to the NSW Central Cancer Registry by hospitals, pathology laboratories, and radiotherapy departments. 2sBecause delays in the routine notification process would have led to a greater loss of cases due to deteriorating health or death, monthly telephone calls were made to urologists throughout NSW for earlier ascertainment of cases. In the period up to 31 July 1991 (allowing for late notifications), 744 eligible cases of RCC and 200 of CaRP were identified. In the succeeding eight months, 24 additional cases were notified indicating that 97 percent of all cancers diagnosed within the study period were included in the case population. Permission for inclusion of an eligible case in the study was requested from the attending doctor, followed by a letter to the individual inviting participation. The release of information from the Cancer Registry was made conditional upon adherence to a strict protocol which did not permit repeated approaches to either the doctor or the patient, nor could information be obtained from relatives of the patients. For RCC, attrition due to death (23 percent), refusal (doctor, two percent; patient, one percent) or nonresponse (doctor, one percent; patient, five percent) resulted in a case group comprising 322 men and 181 women. For CARP, 59 men and 90 women were interviewed, death (15 percent), refusal by doctor (one percent), or patient (five percent), and nonresponse by doctor (three percent) or patient (two percent) accounting for the remainder. In each of the 12 fiveyear age groups between 20 and 79 years, the percentages of the potential RCC cases who participated were 80, 100, 83, 77, 79, 78, 75, 79, 74, 65, 55, and 47 respectively. For CARP, the percentage who participated in the nine five-year age groups between 35 and 79 years were 100, 100, 89, 89, 84, 90, 74, 58, and 59. The majority of the cases fell in the four highest five-year age groups. 26 The diagnosis of interviewed cases was based on histopathology of the kidney (87 percent RCC, 92 percent CARP) or other tissue (one percent RCC), fine-needle aspiration cytology of the kidney (four percent RCC), or by computerized tomography, ultrasound, or contrast radiography (eight percent of each cancer). Of the proportional random sample (n=1,090) obtained from the current electoral rolls for the state of NSW, telephone numbers were found for 803. An initial letter seeking participation in the study was fol-
Urologic disease and kidney cancer lowed, if necessary, by a second letter and up to 10 telephone calls. The information on the rolls was out of date for 60 subjects (52 moved, eight were dead) and 18 could not speak English. Of the remaining 725, 74 percent were interviewed, the remainder being comprised of refusals (ill health, seven percent; senility, less than one percent; other reasons, two percent; no reason, 16 percent) and nonrespondents (two percent). Among the controls, women who were not interviewed were slightly older than those who were (65 + 8 cf 62 + 9 years, t = 3.092, d.f. = 389, P < 0.001); no such difference was found for men. One trained interviewer carried out all the interviews between May 1989 and July 1991. She was not blind to case/control status but was required to adhere to the wording of the structured questionnaire so that it was not possible to probe cases to a greater degree than controls. Of the cases, all but 10 (seven RCC, three CARP) were interviewed within one year of diagnosis (55, 87, and 69 percent within three, six, and nine months of diagnosis, respectively). Personal interviews were held in the homes of all subjects who lived in the Sydney metropolitan area (256 RCC, 71 CARP, 232 controls). For subjects living in the remainder of NSW (233 RCC, 76 CARP, 291 controls), the checklists to be used in conjunction with the standard questionnaire were mailed with a request to keep them unopened but accessible for subsequent telephone interview. However, while all telephone respondents had kept the checklists at hand, about half had opened them before the interview took place. Self-administered questionnaires were completed by 14 RCC cases, two CaRP cases, and 12 controls as this was the only means by which these subjects would participate. The questionnaire sought information about the regular consumption of prescribed medicines such as diuretics, antihypertensive drugs, oral contraceptives, estrogens, and 'diet' pills; height (without shoes) and weight (usual weight throughout adult life); and a reproductive and medical history, in addition to data about other suspected risk factors and confounders. The type and/or brand of prescribed medicine (according to comprehensive checklists), the usual number taken per day, and the precise period of consumption were sought, explicitly excluding the period after 1 January 1987 for all subjects. Antihypertensive drugs (in this paper not including diuretics, which were analyzed separately) were classified according to their method of action as [3-blockers, a-blockers, vasodilators including calcium antagonists, angiotensin converting enzyme (ACE)-inhibitors, or 'other.' Similarly, diuretics were grouped as thiazide, loop, or 'other.' 'Diet' pills included amphetamines as well as appetite suppressants. Nonconsumers of prescribed
drugs were defined as those who had taken less than 'two tablets a week for two weeks or longer' before 1987. Subjects were asked if they had ever been told by a doctor that they had certain specified medical or surgical conditions and for the year of diagnosis. Only diagnoses before 1987 were used in the analyses and no validation of the information was performed.
Analysis Initial evaluation included inspection of frequencies of the variables. As the 28 self-administered questionnaires contained an unacceptably high level of missing data, it was decided to restrict the analysis to the 489 cases and 523 controls who were interviewed either face-to-face or by telephone. Tertiles of exposure variables were calculated on the basis of their distribution in the entire control group; tertiles for age were based on cases and controls combined. Body mass index (BMI) was calculated as usualweight/(height) 2for men and usual weight/(height) ~.s for women; 2' tertiles for BMI were derived for men and women separately. Relative risks (RR), together with 92 percent confidence intervals (CI), were estimated from multivariate logistic regression using EGRET 28according to Breslow and Day. 29All estimates of risk were adjusted for age (in tertiles), sex, and method of interview. The effect of each factor and of potential interactions was tested by the likelihood ratio test. Tests for trend were obtained by scoring the levels of the categorized exposure level, disregarding the nonexposed category and treating the scored variable as continuous. All factors with a statistically significant influence or for which there was prior evidence of an association were included in the final model which estimated the effect of each factor adjusted for all other significant factors.
Results Cases and controls are described in Table 1 with respect to the percentage (age-adjusted to the total population of subjects) in whom there had been a diagnosis, before 1987, of various medical and surgical conditions chosen because in previous studies they had been linked with kidney cancer. Table 2 gives similarly age-adjusted percentages of regular consumption of antihypertensive drugs, diuretics, potassium supplements, 'diet' pills, oral contraceptives, and estrogens. RRs (adjusted for age, sex, and method of interview) given in Tables 3 (for diagnoses), 4 (for drugs), and 5 (for obesity) show significantly increased risks associated with hypertension, potassium supplements, 'diet' pills, and obesity (RCC only); kidney infection (CARP only); kidney stones, kidney injury, antihypertensive drugs, and diuretics (both types of Cancer Causes and Control. Vol 3. 1992
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M. McCredie and J. H. Stewart T a b l e 1. Medical h i s t o r y ' - - p e r c e n t a g & of cases and controls, N e w S o u t h Wales, 198%90 Population controls
Hypertension Angina Heart attack Stroke Kidney stones Bladder stones Kidney infection Bladder infection Kidney injury Diabetes Thyroid disease
Renal cell cancer
Renal pelvic cancer
Males (n = 231)
Females (n = 292)
Males (n = 310)
Females (n = 179)
Males (n = 58)
Females (n = 89)
25.1 13.4 12.9 3.5 13.2 2.6 5.0 27.2 5.1 4.0 1.8
39.7 7.8 4.8 2.0 7.1 0.7 19.1 52.1 2.6 6.2 12.5
41.6 14.4 13.6 5.2 20.0 2.6 7.1 22.7 14.9 6.6 3.8
45.2 9.2 6.2 1.6 5.9 0 17.8 48.3 12.2 7.7 17.1
28.3 6.0 12.0 7.4 27.0 2.0 10.6 25.3 19.6 9.2 1.4
40.2 14.4 11.6 2.4 10.3 3.0 33.1 44.1 5.5 5.4 9.0
' Diagnosed before 1987. Age-adjusted to the total population of study subjects.
T a b l e 2. Regular c o n s u m p t i o n of prescribed medicines~---percentage b of cases and controls, N e w South Wales, 1989-90 Population controls
Antihypertensive drugs Diuretics Potassium supplements 'Diet' pills Oral contraceptives Estrogens
Renal cell cancer
Renal pelvic cancer
Males (n = 231)
Females (n = 292)
Males (n = 310)
Females (n = 179)
Males (n = 58)
Females (n = 89)
22.9 18.6 8.8 1.6
29.6 38.0 20.0 10.1 40.8 24.1
39.3 29.4 13.9 6.3 ---
44.0 47.0 26.4 15.8 31.3 15.9
26.3 13.1 5.7 4.8 ---
55.6 55.9 28.7 9.0 29.5 10.0
Taken before 1987. b Age-adjusted to the total population of study subjects.
T a b l e 3. Risk ratios (RR) • for k i d n e y cancer associated w i t h diseases diagnosed before 1987, N e w S o u t h Wales, 1989-90 i
Renal cell cancer
No. of
exposed controls Hypertension Angina Heart attack Stroke Kidney stones Bladder stones Kidney infection Bladder infection Kidney injury Diabetes Thyroid disease
178 56 45 14 49 8 66 219 20 26 38
' Adjusted for age, sex, method of interview. b CI = 95% confidence interval.
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Renal pelvic cancer
No. exposed
RR
(CI) b
No. exposed
RR
(CI) b
203 56 51 18 73 7 57 153 70 31 41
1.8 1.1 1.1 1.3 1.5 0.7 1.1 0.8 3.8 1.4 1.6
(1.3-2.3) (0.7-1.6) (0.7-1.7) (0.6-2.7) (1.0-2.2) (0.3-2.0) (0.8-1.7) (0.6-1.0) (2.3-6.4) (0.8-2.5) (1.0-2.6)
57 20 20 8 25 4 35 58 17 11 11
1.2 1.1 1.5 1.7 2.0 2.0 2.3 0.8 3.3 1.5 1.0
(0.8-1.8) (0.6-2.0) (0.9-2.7) (0.7-4.2) (1.2-3.5) (0.6-7.1) (1.4-3.8) (0.6-1.2) (1.7-6.7) (0.7-3.0) (0.5-2.0)
Urologic disease and kidney cancer Table 4. Risk ratios (RR)' for kidney cancer associated with prescribed medicines,New South Wales, 1989-90
Antihypertensive drugs Diuretics Potassium supplements 'Diet' pills
Renal pelvic cancer
Renal cell cancer
No. of exposed controls 143 156 78 32
No. exposed
RR
(CI) b
No. exposed
RR
(CI) b
191 171 87 50
2.0 1.7 1.5 2.1
(1.5-2.7) (1.2-2.2) (1.1-2.2) (1.3-3.5)
69 63 32 11
2.0 1.6 1.4 1.3
(1.4-3.0) (1.1-2.4) (0.9-2.3) (0.6-2.6)
a Adjusted for age, sex, method of interview. b CI = 95% confidence intervals.
Table 5. Risk of renal cell cancer associated with obesity, New South Wales, 1989-90 BMI c
Males No. of controls
74 Low 73 Medium 76 High Unknown 8 Test for trend a
No. of cases 88 78 141 3
Females RR a
(CI) b
1 1.0 (0.6-1.5) 1.6 (1.1-2.5) 0.3 (0.1-1.3) 5.55, P = 0.018
No. of controls
No. of cases
95 94 98 5
50 59 64 6
RR a
Males and females (CI) b
1 1.2 (0.8-2.0) 1.3 (0.8-2.1) 2.5 (0.7-8.8) 1.10, P = 0.294
No. of controls
No. of cases
169 167 174 13
138 137 205 9
RR'
(CI) b
1 1.1 (0.8-1.5) 1.5 (1.1-2.0) 0.9 (0.4-2.2) 6.05, P = 0.014
RR = risk ratio model adjusted for age, sex, method of interview. b CI = 95% confidence interval. c BMI, body mass index, calculated as usual weight/height2 for men and usual weight/height *,5for women; tertiles were 25.34 for men and 30.79 for women. d X2 excludes unknown category.
cancer). A history of bladder infection was related to a reduced risk of RCC. However, when further adjustment was made in the logistic regression model for each of these factors and for cigarette smoking, and obesity (RCC) or phenacetin-containing analgesics (CARP), many of the risk estimates lost their statistical significance (Table 6).
Diuretics When adjusted for antihypertensive drugs (as well as age, sex, method of interview, smoking, and obesity [RCC] or phenacetin consumption [CARP]), diuretics (all types considered together) no longer increased the risk for RCC (RR= 1.2, CI=0.9-1.7) or CaRP (RR --- 1.2, CI = 0.8-1.9). When the analysis for RCC was restricted to women in whom no diagnosis of hypertension had been made prior to 1987 and who had not taken antihypertensive drugs, no increased risk was found for women of any age (RR = 1.2, CI = 0.71.9) or for those aged less than 59 years (the lowest terfile; RR = 1.6, CI = 0.7-3.6). Of subjects who had ever taken diuretics, the majority also had taken antihypertensive drugs at some time (controls, 55 percent; RCC, 73 percent; CARP, 79 per-
cent). Similarly, most subjects who ever took antihypertensive drugs, also had taken diuretics (controls, 60 percent; RCC, 65 percent; CARP, 75 percent). Separate analyses were carried out for diuretic use among those who had, and those who had not, taken antihypertensive drugs, and also among those who had, and those who had not, reported hypertension. In none of these groups did diuretic use significantly increase the risk of RCC or CARP. Compared with those who had never used diuretics regularly, no trend was found in risk for RCC with the number of years before diagnosis that diuretics were first taken, the risk estimates being 0.8 (CI = 0.4-1.2), 1.2 (CI = 0.8-1.9) and 1.3 (CI = 0.8-2.2) for 1-8, 9-15 and 16 or more years, respectively. For neither type of cancer was there any association with thiazide, loop, or 'other' diuretics, once adjustment had been made for the effect of antihypertensive drugs. Potassium supplements, which were almost invariably taken with diuretics, did not independently alter the risk for RCC or CARP. The reason given for taking diuretics was 'to lose weight' by only two percent of each group of subjects; 'to lower blood pressure' by 53 percent (RCC), 42 perCancer Causes and Control. Vol 3. 1992
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M. McCredie and J. H. Stewart Table 6. Mutually adjusted risk factors* for kidney cancer, New South Wales 1989-90
Table 7. Risk of renal cell cancer associated with hypertension, New South Wales, 1989-90
Renal cell cancer
No. of exposed
Hypertension D-blockers Kidney stones Kidney infection Bladder infection Kidney injury Thyroid disease 'Diet' pills
RR b
(CI) o
1.6 1.5 1.5 0.9 0.7 3.6 1.5 2.1
(1.1-2.2) (1.0-2.3) (1.0-2.3) (0.6-1.4) (0.5-0.9) (2.1-6.2) (0.%2.6) (1.2-3.5)
Renal pelvic cancer RR d
(CI) c
2.0 1.3 1.7
(1.2-3.4) (0.7-2.4) (1.0-3.1)
3.3
(1.5-7.4)
"Also adjusted for age, sex, method of interview, and cigarette smoking. b RR = risk ratio adjusted for (a) and body mass index. ° CI = 95% confidence interval. d R R = r i s k ratio adjusted for (a) and phenacetin-containing analgesics. ' Not included in final model as no a priori link with CaRP and no association demonstrated in preliminary analyses.
Hypertension Never diagnosed A 1980-86 A 1970-79 A 1940-69
Controls Cases 344 79 48 51
268 86 50 67
RR'
(CI) b
1 1.5 1.4 1.8
(1.0-2.3) (0.9-2.3) (1.1-2.9)
' RR = risk ratio, model adjusted for age, sex, method of interview, body mass index, smoking, p-blockers, bladder infections, kidney injury, and 'diet pills'. b CI = 95% confidence intervals. A = diagnosis.
For neither RCC nor CaRP did the risk rise significantly with increasing years of consumption of [3-blockers.
Hypertension cent (CARP), and 46 percent (controls); 'for heart disease' by five percent, zero and three percent; and 'to reduce swelling' by 38 percent, 53 percent, and 48 percent, respectively; other reasons comprised the remainder.
Antihypertensive drugs Regular consumption of antihypertensive drugs (all types considered together) remained a significant risk factor for RCC when, in addition to age, sex, method of interview, smoking, and obesity, terms for diuretics and potassium supplements were included in the model (RR = 2.0, CI = 1.4-2.7) and when the presence of hypertension was taken into account (RR--1.5, CI = 1.0-2.2). When B-blockers, oL-blockers, vasodilators, ACE-inhibitors, and 'other' antihypertensive drugs were entered simultaneously into a logistic regression model (adjusted for age, sex, method of interview, obesity, and smoking), 13- and o~-blockers significantly increased the risk for RCC (RR = 1.8, CI = 1.3-2.6; and RR = 1.6, CI = 1.1-2.4, respectively). However, in a full model containing terms for hypertension and all other significant risk factors, only [3-blockers increased the risk (RR = 1.5, CI = 1.0-2.3), and this seemed to occur in women (RR= 1.8, CI=1.0-3.2) rather than in men (RR=I.3, CI = 0.7-2.3). Similarly, in a model containing terms for all significant risk factors for CARP, it was regular consumption of f3-blockers rather than other antihypertensive drugs that increased the risk (RR = 1.8, CI = 1.1-2.9), and again the effect was seen in women (RR=3.2, CI = 1.7-6.2) but not men (RR = 0.8, CI = 0.3-2.1). 328
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The estimate of risk for RCC associated with a diagnosis of hypertension before 1987 was reduced but remained significant after adjustment for B-blockers and all other risk factors (RR = 1.6, CI = 1.1-2.2; Table 6), the effect being apparent in men (RR=2.3, CI = 1 . 4 - 3 . 6 ) rather than women (RR = 1.2, CI = 0.71.9). When duration of hypertension was grouped into tertiles, although no clear 'dose-response' was seen, there was an increased risk in each category and those whose hypertension had been diagnosed for more than 20 years had the highest risk (RR = 1.8, CI = 1.1-2.9; Table 7).
Urologic disease Injury to the kidney showed a threefold increased risk of each type of kidney cancer (Table 6). Lower urinary tract infections appeared to decrease the risk of RCC (RR = 0.7, CI = 0.5-0.9). Once the effect of other risk factors had been taken into account, the association with kidney stones was stronger in men (RR = 1.8, C I = 1.1-3.0 for RCC; RR=2.0, CI=0.9-4.6 for CARP) than in women (RR = 0.9, CI---0.4-2.2 for RCC; RR = 1.1, CI = 0.4-3.2 for CARP). However, it was in women rather than men that there was some association of kidney infection with CaRP (RR = 1.9, CI=0.9-3.8 in women; RR=0.9, CI=0.2-3.2 in men).
Other diseases related to hypertension Neither angina, heart attack, nor stroke significantly increased the risk for RCC, the point estimates being 1.1,1.1, and 1.3, respectively. Nor was an association of these diseases found with CARP, although the esti-
Urologic disease and kidney cancer mates of risk were somewhat higher for heart attack (RR=I.6, CI=0.9-2.8) and stroke (RR=I.6, CI = 0.6-4.1) than for angina (RR = 1.0).
Obesity Compared with subjects in the lowest tertile of body mass index (BMI), there was a rising risk of RCC with increasing measure of obesity (Table 5). The highest risk was seen in the upper tertiles of BMI both for men and for women when considered separately. 'Diet' pills (when adjusted for all other significant factors, including obesity) increased the risk for RCC (RR = 2.0, CI--1.2-3.4), the risk in men (RR = 2.5, CI = 0.8-7.8) appearing to be higher than in women (RR -- 1.5, CI = 0.8-2.7). No link with obesity or 'diet' pills was found for CARP.
Hormonal factors Several endocrine-related factors were examined in women in relation to the risk for RCC. Neither age at menarche nor age at natural menopause was associated with this cancer. Having a hysterectomy increased the risk of RCC (RR = 1.8, CI--1.2-2.7) but bilateral oophorectomy did not (RR=I.4, CI=0.8-2.4). Neither age at hysterectomy nor age at oophorectomy showed a trend in risk. Nonsignificant associations ( P = 0.10) with RCC were found for regular use of oral contraceptives (RR = 0.7, CI = 0.4-1.1) and regular use of estrogens (RR = 1.4, CI = 0.9-2.1) but, for each type of drug, no gradation in risk was seen when terms for 'age at startrag' and 'duration of use' were incorporated simultaneously in a logistic model. Having borne at least one child reduced the risk of RCC (RR = 0.6, CI = 0.3-1.1) but when the effects of 'age at first child' and 'number of children' were examined together, no trends in risk were found. Adjustment for obesity, cigarette smoking, and the hormonal factors resulted in the risk for RCC associated with each of these hormonal variables becoming less significant.
Thyroid disease and diabetes No link with diabetes was found for either type of kidney cancer. Thyroid disease was not related to CARP, and adjustment for all significant risk factors lessened its apparent association with RCC (RR--1.5, CI = 0.9-2.6).
Discussion o f the conditions examined here, only kidney injury (for both types of kidney cancer), kidney infection (for
CaRP only), and hypertension (for RCC only) appeared to increase the risk for renal cancer, the other associations losing their statistical significance when the effects of possible confounding factors were taken into account. While the RRs associated with kidney injury are relatively high (about three for each cancer), this is a situation in which recall bias is likely, and the finding, as in previously published studies, 1,4,9must be regarded as provisional. A history of kidney infection may be merely a marker for the presence of another precancerous condition, the most likely candidate being renal papillary necrosis, which frequently manifests only as a tendency to pyelonephritis and, in Australia, is much more common in women (in whom an association with infection was found in this study) than men. That the link between RCC and high blood pressure was increased by the duration of recognized hypertension strengthens the likelihood that this condition contributes directly or indirectly to the causation of RCC, rather than appearing as a result of the kidney tumor. The definition used for this study, 'hypertension diagnosed by a doctor as reported by the subject,' is used frequently and has been validated in the US 3°but not in Australia. The extent to which the risk of RCC posed by hypertension was not from the disease itself, but from its treatment, was addressed in the multivariate analysis. Subjects diagnosed with hypertension during 1940-69 had the greatest risk of RCC (Table 6) but the suggestion that thiazide diuretics might be responsible was not supported. These diuretics were introduced in NSW only in the late 1950s, their major use for the treatment of hypertension being in the 1970s. During most of the past two decades, J3-blockers and diuretics, separately or combined, have been the most frequently prescribed drugs for high blood pressure. Unlike previous studies,6,7 here diuretics did not independently increase the risk for kidney cancer, either when used as a treatment for hypertension, or when taken by women who did not have hypertension. The initial report of a link between diuretic use and RCC was in women under the age of 55 years; we could find no association in general, in women, or in our lowest age group (under 59 years). Only two percent of subjects reported taking diuretics specifically to lose weight. In both forms of kidney cancer, the case for an etiologic role for [~-blockers independently of hypertension is weakened by the association being found predominantly in women. Duration of exposure was not related to risk, but no measure of intensity of exposure could be applied because of variation in the dose taken by individual patients, and the many different J3-blockers used. About 20 percent of controls Cancer Causes and Control. Vol 3. 1992
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M. McCredie and J. H. Stewart and 10 percent of cases who took 13-blockers did not have hypertension; coronary heart disease is the other common reason for taking these drugs. Neither of the common extra-renal diseases associated with hypertension, coronary heart disease (recorded here as angina or heart attack), or stroke, showed a positive relationship to either form of kidney cancer. Women with CaRP did have a history of angina or heart attack about twice as frequently as female controls or cases of RCC, but this could not be attributed, contrary to what might have been expected, to a link with smoking or analgesic abuse. Diseases of the bladder were not associated with an increased risk of either form of kidney cancer; in fact, the risk was reduced in those giving a history of bladder infection. As it is difficult to envisage a protective role of bladder infection itself, one must consider the possibility that cystitis is more likely to occur in people who, for unrelated reasons, have a reduced likelihood of kidney cancer. Both obesity and regular use of 'diet' pills were confirmed as risk factors for RCC but, in this study, no links could be found with either diabetes or thyroid disease. 'Diet' pills were taken for mental stimulation, rather than for reducing weight, only by a minority of subjects. Regarding factors related to female reproductive history, a pattern emerged of a decreased risk associated with use of oral contraceptives or having borne children, and an increased risk with taking estrogens, or having had either hysterectomy or bilateral oophorectomy. However, none of these relationships was significant in the multivariate analysis. No casecontrol study has examined the link between oral contraceptives and RCC, but three cohort investigations also failed to find an association. 31 Selection bias in this study must be considered because of nonparticipation among cases due to illness or death (23 percent RCC; 15 percent CARP) and of nonresponse among the controls (26 percent). Cases and female controls who were not interviewed were slightly older than those who were interviewed. Apart from these observations, we could not determine the extent to which bias was introduced as we had no measure of social class (apart from unsatisfactory groupings based on postcode of residence) and no access to medical records. Detailed analysis of selection bias in another study of RCC 32found higher socioeconomic class and a history of renal stones to be predictors of participation by both cases and controls; obesity in women, hypertension, and nonsmoking to be predictors in cases only; and heart disease to be associated with control participation and case nonparticipation. Thus, doubts were cast on the risk estimates for obesity in women and hypertension; it is conceivable that simi330
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lar bias could negate the findings from the current study with respect to these factors. The NSW electoral rolls, as a source of populationbased controls, have the drawback that they are updated only every six months to three years depending on the area in which an election is to be held. Electoral enrolment is compulsory for all persons over the age of 18 years who were born in, or who have become permanent residents of, Australia; thus people not on the electoral roll are, for the most part, recent immigrants and transient residents, some of whom would not be fluent in English. In NSW, 97 percent of households have the telephone connected. Although the telephone company will not release any details about 'unlisted' telephone numbers, seven to 12 percent of telephones in NSW, depending on the area, are not listed in the directories? Greater proportions of 'unlisted' telephones are in urban than rural areas, and in suburbs of higher socioeconomic class. Separate analysis of face-to-face and of telephone interviews identified no systematic bias with respect to use of prescribed medicines or self-reported medical conditions despite the fact that about half of the telephone respondents had seen the checklist of drugs before the interview began? 4 However, it is possible that there was differential reporting between cases and controls. Because hypertension is so common among middleaged people in Western societies, the population attributable risk (16 percent) is second only to that for smoking as an etiologic factor for RCC. 1," Obesity, which is also a common problem of modern society, is associated with the same magnitude of risk for RCC; the population attributable risk for our definition of obesity (the highest tertile) was 13 percent. While the associations between these two conditions and RCC may be indirect, relating to lifestyle exposures such as diet and exercise or to an inherited predisposition, the links with hypertension and obesity may explain why the incidence of cancer of the kidney is increasing faster than almost any other malignancy.36,37 Acknowledgements--We are grateful to Professor D. Raghavan, now at Roswell Park Cancer Institute, Buffalo, NY (US) for his participation in the design of this study; to the urologists of New South Wales for permission to include their patients in this study; to Joy Gillies for conducting the interviews with all the cases and controls; and to Lesley Porter for coding the questionnaires and all data entry.
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