EPIDEMIOLOGY AND RISK FACTORS OF KIDNEY CANCER

This review article presents kidney cancer epidemiology as well as main environmental and life style risk factors.


INTRODUCTION
Kidney cancer is the most important cancer site because of high lethality rates and increasing incidence in some parts of the world mainly among all Caucasian populations and in Japan.There were approximately 189 000 kidney cancers in the year 2000 worldwide, two-thirds of which occurred in developed countries 1 in connection with higher prevalence of diff erent risk factors.
The majority of cancers among adults, which arise in the renal parenchyma, are adenocarcinomas, for the most part of proximal tubular origin, although nephroblastoma occurs in children (Wilms' tumour).Adenocarcinomas may be separated into clear cell and granular cell carcinomas, although the 2 cell types may occur together in some tumors.The distinction between well-diff erentiated renal adenocarcinomas and renal adenomas can be diffi cult.The diagnosis is usually made arbitrarily on the basis of size of the mass, but size alone should not infl uence the treatment approach, since metastases can occur with lesions as small as 0.5 centimeters.
The highest incidence of kidney cancer is observed in the Czech Republic, with rates of approximately 22 per 100 000 in men and 11 per 100 000 in women.High rates are also observed in Estonia, Hungary, Slovakia, Lithuania, Latvia and Germany (Table 1) and among some black populations of the USA.Conversely, rates up to 10 to 15 times lower are reported in most Asian and African populations and some of South American populations.
The incidence in males is approximately twice that among females in most populations.The incidence of kidney cancer increases logarithmically from the age of 30 years and plateaus around the age of 60-70.
The highest mortality of kidney cancer is reported in the Czech Republic, with rates of approximately 10 per 100 000 men and 4.5 per 100 000 women.High rates of mortality are also reported in Lithuania, Estonia, Iceland, Latvia, Hungary, Slovakia and Germany (Table 1).The probability of cure is directly related to the stage or degree of tumor dissemination.Even when regional lymphatics or blood vessels are involved with the tumor, a signifi cant number of patients can achieve prolonged survival and probable cure 2 .When distant metastases are present, disease-free survival is poor, although occasional selected patients will survive after surgical resection of all known tumor.Since a majority of patients are diagnosed when the tumor is still relatively localized and amenable to surgical removal, approximately 40 % of all patients with renal cancer survive 5 years.
This review focuses exclusively on renal cell cancer, because the other urinary cancers (renal pelvis, ureter and urethra) are much rarer and histologically more similar to those of the bladder than the renal parenchyma cancer.Also their aetiology is likely to be more similar to the aetiology of bladder cancer.

SITUATION IN THE CZECH REPUBLIC
Malignant tumors of the kidney (apart from renal pelvis) account for about 4.5 % of all malignant tumors in the Czech Republic 3 .Kidney cancer is the 4 th most common cancer in males and 7 th most common cancer in the female population in the Czech Republic (Table 2).The highest incidence in the year 2001 was observed in the age range 65-85 and older in both males and females (Table 3).There is no clear-cut trend within the last eight years since 1994 to 2001 in either kidney cancer incidence or mortality (Table 4).As far as geographical distribution of kidney cancer in diff erent regions of the Czech Republic is concerned, the highest incidence is observed in South -Western Bohemia Regions (Plzeňský kraj, Jihočeský kraj and Kraj Vysočina).Conversely the lowest incidence is observed in North -Western Regions (Liberecký kraj, Karlovarský kraj, Moravskoslezský kraj, Královehradecký kraj and Ústecký kraj) of the Czech Republic (Fig. 1).

RISK FACTORS
Almost all information on risk factors for renal cell cancer has come from case-control studies, conducted in a number of countries in North America, Europe, Australia and Asia.
There are not only life-style risk factors like smoking, diet and obesity, alcohol and other drinks, use of diff erent drugs etc., but environmental risk factors like occupational exposure to diff erent chemicals, radiation, renal dialysis as well, participating probably in the etiology of kidney cancer.

Smoking
Although results from case-control studies are not entirely consistent, a convincing relation between cigarette smoking and renal cancer has been found 4 .Cohort studies also support this association 5 .
Cigarette smoking has been consistently found to be a moderate risk factor for kidney cancer.Increased risk compared with non-smokers has been observed in the order of 1.2 to 2.3.
There has been a dose-response relationship demonstrated 6 with increasing cigarette consumption, with risk for heavy smokers ranging from 2.0 to 3.0.The risk appears to decline with increasing years of smoking cessation 7 .
Population attributable risk estimates indicate that cigarette smoking, both past and present, is responsible for between 27 and 37 % of kidney cancer cases among men, and between 10 and 24 % of cases among women.Approximately half of this attributable risk is due to current smoking.
Another study has reported a suggestive association of passive smoking with renal cell cancer 6 .

Obesity
Virtually every study that has examined body weight and renal cell cancer has observed a positive association.
Obesity has been consistently linked with kidney cancer, especially among women 8 , with less consistent and weaker results among men 9 .It is not clear what is the mechanism by which obesity causes kidney cancer.Hormonal changes such as increased levels of endogenous estrogens in obese persons may be responsible.Although estrogens induce renal cancer in certain laboratory animals 10 , there is scant epidemiological evidence linking hormone-associated variables to renal cell cancer.Obesity may also predispose to arterionephrosclerosis, which may, in turn render the renal tubules more susceptible to carcinogenesis.Moreover, obesity is sometimes treated with diuretics, which are under evaluation as a potential risk factor (see below).
The population attributable risk of kidney cancer associated with excess weight (defi ned as being in one of the last three quartiles of body mass index) has been estimated to be over 40 % in women and 5 % in men.

Analgesics
Although heavy use of phenacetin-containing drugs has been clearly linked to renal pelvis tumors 11 , an association has been reported also for renal cell cancer 12,13 .Confounding factors do not explain the association because adjustment has been made for cigarette smoking and the use of other types of analgesics.
There have been inconsistent fi ndings on the role of aspirin in the etiology of renal cell cancer.A large-scale study in Minnesota 14 observed no relation with regular use or duration of use for aspirin, acetaminophen or even phenacetin.But in Denmark, women who were heavy users of phenacetin had a signifi cant fi ve-fold increase in the risk of renal cell cancer 15 .This study also observed no signifi cantly increased risk for aspirin or acetaminophen users.

Diuretics
Diuretic use has been associated with a fi ve-fold increase in the risk of renal cell cancer among women 16 .
Adjustment for blood pressure status made little diff erence, because both hypertensives and non-hypertensives were at elevated risk.Some cohort studies have also linked renal cell cancer with diuretic use 17 .Recent medical records-based case-control studies using prescription data from patients' charts have found three-to four-fold increased risks among women after adjustment for known confounders, including hypertension 18,19 .It is noteworthy that animal studies have linked hydrochlorothiazide and furosemide, the most commonly used diuretics, with tubular cell adenomas and adenocarcinomas of the kidney in rats and hepatocellular tumors in mice [20][21][22] .Moreover, these compounds act on the renal tubules, the site of origin for renal cell cancers.In many countries of the world, the use of diuretics has increased in the last decades and is especially common among the elderly, so its role, if causal, would have major public health implications as a result of the widespread use of these drugs.

Estrogens
Although estrogens have induced renal cell carcinomas in laboratory animals, there is little epidemiological evidence supporting an association in humans 23 .Weakly positive fi ndings have been reported for menopausal estrogen use 24 and oral contraceptives 6 .The relation in humans between hormone-related variables and renal cell cancer remains still unclear.

Hypertension
Hypertension has also been linked to kidney cancer, although the strength of this relationship has generally been greatly reduced after adjustment for use of diuretics and other antihypertensive drugs.These fi ndings suggest that use of medications may be the primary risk factor and not hypertension per se.Both diuretic and non-diuretic antihypertensive medications have been linked to kidney cancer, with supportive evidence from animal studies.However, identifying whether the real risk is due to the hypertensive state or due to antihypertensive medication has not so far been possible.Whichever of the two is the real risk factor, it is likely to account for a substantial proportion of cases.The attributable risk of reported hypertension or treatment with antihypertensive drugs has been estimated to be 21 % overall, and 39 % among women.

High protein consumption
High protein consumption from meat 25 and dairy 26 products has been associated with chronic renal conditions that may predispose to kidney cancer, and has been associated with an increased risk of kidney cancer 27 , although the evidence is inconsistent.There may be some biologic plausibility to a high protein diet aff ecting risk of renal cell cancer, because animal studies have shown protein intake can induce renal tubular hypertrophy 28 .(On the other hand a possible protective eff ect has also been identifi ed in a number of studies for high consumption of vegetables).

Coff ee, Alcohol, and Other Beverages
Correlation studies have suggested a relation between the distribution of kidney cancer and per capita consumption of coff ee but the fi nding has not been fully confi rmed by case-control studies, when adjustment is made for the confounding eff ect of cigarette use 29 .Two studies have suggested a positive association.A two-fold risk in both sexes combined was associated with use of decaff einated coff ee without dose-response 30 , while an increased risk for regular coff ee use was seen among women only, again with no dose-response relation 16 .On the other hand, the results of a cohort study in Norway, an area of heavy coff ee intake, showed a signifi cant inverse trend, with consumers of seven or more cups having one fourth the risk of those drinking two or fewer cups daily 31 .Overall, the results of analytical studies indicate that coff ee consumption does not increase the risk of renal cell cancer.
Correlation studies have also reported a relation between per capita intake of alcohol and kidney cancer mortality, but analytical studies of renal cell cancer do not support these fi ndings 32 .The recent Danish casecontrol study observed a statistically signifi cant inverse association of alcohol consumption with renal cell cancer risk 4 .Moreover, cohort studies of alcoholics and brewery workers have reported no excess mortality from kidney cancer 33 .
An increased risk among tea drinkers has been reported in a few studies of renal cell cancer, particularly among women 34 .Also a mortality follow-up of London men revealed a dose-response relation between tea consumption and kidney cancer mortality 35 .In spite of the fact that some teas have been found to be mutagenic and contain tannins that appear carcinogenic in laboratory animals 36 , the etiologic signifi cant of these fi ndings is not clear.

Occupation
Renal cell cancer is not generally considered an occupationally associated tumor, but an excess risk for renal cell cancer has been observed in a variety of occupations with exposure to:

Asbestos
Two cohort studies, one of insulators 37 and one of asbestos products workers 38 reported signifi cantly elevated mortality rates for kidney cancer.Also an association between asbestos exposure, mostly from work in shipyards, and renal cell cancer was suggested in a Boston-area case-control study 39 .There is some evidence from autopsy surveys and animal studies that asbestos fi bers can be deposited in the kidney 40 .Most case-control studies of renal cell cancer have found no association with asbestos exposure, however although their power to detect risks for asbestos exposure is generally low because of the small number of exposed workers.

Polycyclic aromatic hydrocarbons
Coke and coal oven workers exposed to high levels of polycyclic aromatic hydrocarbons have been reported to Epidemiology and risk factors of kidney cancer be at increased risk for kidney cancer 41 .Two case-control studies however observed little excess risk for these workers 42,43 .Also fi re-fi ghters and asphalt and tar workers are exposed to polycyclic aromatic hydrocarbons.

Tetrachloroethylene
Mortality studies have suggested that laundry and dry cleaning workers may be at increased risk for kidney cancer 44 .Also case-control studies have indicated an excess risk among dry cleaners 43 .However a large-scale cohort study of these workers showed no increased mortality from kidney cancer 45 .Dry cleaners have been exposed to a large number of chemicals, notably tetrachloroethylene, which has produced hepatocellular carcinomas in laboratory animals 11 .

Gasoline and other petroleum products
Oil refi nery workers and petrol station attendants have been suggested to be at increased risk for kidney cancer.But recent reviews of cohort studies found little or no evidence of an excess risk of kidney cancer 46,47 .Gasoline came under suspicion as a risk factor for renal cell cancer when male rats exposed long-term to vapors of unleaded gasoline developed a signifi cant excess of renal cancers 48 .A number of epidemiological studies have examined the eff ect of gasoline exposure with inconsistent results 42,[49][50][51] .
Several other occupational associations have been reported like newspaper pressmen, paperboard printing workers, lumberjacks, leather tanners, shoe workers, health care workers, truck drivers, electric power utility workers and architects, with unclear results.
Overall the evidence for associations of kidney cancer with specifi c occupational exposures is still inconclusive.

Hemodialysis
There is an increased incidence of acquired cystic disease of the kidney, which predisposes to renal cell cancer among patients undergoing renal dialysis, especially in men 52 .Although the carcinogenic mechanism is uncertain, some aspect of the uremic process is probably involved during the long-term kidney failure.Some patients with chronic (long-term) kidney failure who are treated with dialysis over a long period of time may develop cysts in their kidneys.Renal cell cancers may develop from the cells that line these cysts.

Radiation
Ionizing radiation appears to increase the risk of renal cell cancer, especially among patients treated for ankylosing spondylitis and cervical cancer, but the eff ects are weak 53 .An increased risk has also been described among patients receiving radium 224 for bone tuberculosis and ankylosing spondylitis 54 .

Genetic factors
Familial clustering of renal cell cancer has been described.Some patients with renal cell cancer may have inherited one or more genes that increase their risk for this disease.The exact function of these genes and how they cause renal cell cancer are not completely known.This hereditary form of renal cell cancer usually occurs in both kidneys and causes multiple tumors to appear.Hereditary forms of renal cell cancer have been found involving both clear cell and papillary cell type renal cell cancer although the specifi c mutations causing these tumors are diff erent.These observations suggest that the origins of renal cell cancer may involve several tumor suppressor genes on the short arm of chromosome 3 (ref. 55).
Recently, researchers have found gene mutations that cause some rare syndromes such as tuberous sclerosis 56 and Von Hippel-Lindau 57 .People with these mutations have an increased risk of developing of kidney tumors.
Von Hippel-Lindau syndrome (VHL) is characterized by multiple tumors of the kidneys, brain, spine, eyes, adrenal glands, pancreas, inner ear, or epididymis.Von Hippel-Lindau disease occurs in about 1 in 36,000 births and tends to occur in clusters within families.VHL patients have high incidence of developing clear cell renal cell cancer and the cancers usually develop at an early age.About 40% of people with this disease have either cysts or tumors in both kidneys.Some can have many small renal cell cancers throughout their kidneys.The gene that causes von Hippel-Lindau disease has been found and is called the VHL gene.It is located on chromosome 3. Tests looking for the VHL gene mutation are becoming available.It has also been shown that a high number of sporadic clear cell renal cell cancer show genetic alterations involving VHL gene thus underscoring the importance of this gene in the pathogenesis of clear cell renal cell cancer.
Tuberous sclerosis is characterized by numerous bumps on the skin (caused by small tumors of the blood vessels), seizures, mental retardation, and cysts in the kidneys, liver and pancreas.Patients with this disease also have an increased risk of developing renal cell cancer.
Some other studies have also shown an association with blood group A.

Other risk factors
There has been a clear-cut association found between herpes-type virus and renal tumors in the toad.Although nearly all toads carry the infection, only 10 % of animals developed tumors.These fi ndings led to a search in human renal tumors for the evidence of herpes virus proteins.Although herpes simplex proteins were found in the only study reported to date 58 , these observations should be repeated.

PREVENTION
The main avoidable causes of kidney cancer are cigarette smoking and excess body weight, which together account for up to 50 per cent of all cases 59 .Primary prevention in reducing cigarette smoking and obesity are therefore the clearest strategies for reducing the incidence of the disease.A substantial proportion of cases are also likely to be related to hypertension although further information on whether the true risk factor is the disease or the treatment is required in order to clarify implications for prevention 60 .

Table 1 .
Kidney cancer incidence and mortality (world standard) in the year 2000.

Table 2 .
New cases of cancer in the Czech Republic in the year 2000.

Table 3 .
Kidney cancer incidence in the Czech Republic in the year 2001 (crude) by gender.

Table 4 .
Kidney cancer incidence and mortality (crude) in the Czech Republic in the period of 1994-2001.