# Epidemiology of Kidney Cancer

Authors: D. Pascual; A. Borque
Journal: Advances in Urology
 (2008)

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## Abstract

Some tumors are known to have a definite cause-effect etiology, but renal cell carcinoma (RCC) is not one of them precisely. With regard to RCC we can only try to identify some clinical and occupational factors as well as substances related to tumorigenesis. Smoking, chemical carcinogens like asbestos or organic solvents are some of these factors that increase the risk of the RCC. Viral infections and radiation therapy have also been described as risk factors. Some drugs can increase the incidence of RCC as well as other neoplasms. Of course, genetics plays an outstanding role in the development of some cases of kidney cancer. Chronic renal failure, hypertension, and dialysis need to be considered as special situations. Diet, obesity, lifestyle, and habits can also increase the risk of RCC. The aim of this review is to summarize the well-defined causes of renal cell carcinoma.


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## Body

## 1. Introduction

Speaking
about cancer, one of the most difficult issues is to find a definite and direct
cause. There are few tumors with a well-known etiology, but renal cell
carcinoma (RCC) is not one of them precisely.In
these cases, we can only try to identify some clinical and occupational
factors, or some substances related to carcinogenesis.Epidemiology
is an important tool to answer many questions about cancer origin. Differences
in age, gender, and geographic distribution have been reported, and multiple
clinical factors related to the development of RCC have been established. Some
of them have been thoroughly demonstrated in experimental models and in vitro
studies, however not all of them recognized as definite etiologic factors.


## 2. Material and Methods

A systematic review search strategy was developed to identify
publications related to epidemiology of renal cell carcinoma. This search
strategy was run in PubMed through the medical subject heading “carcinoma,
renal cell” and the subheading of this descriptor “epidemiology.” We limited
our search strategy to articles published in the previous 5 years, language
English or Spanish, and related to humans.585 articles were found. Abstracts were evaluated and the full text of
articles selected was reviewed. Secondary search from the bibliography of
selected articles was also considered.The European cancer registry-based
study on survival and care of cancer patients (EUROCARE) and our experience was considered. Last review was on 31 of March 2008.


## 3. Demographic Aspects of Renal Cell Carcinoma

Among
urologic tumors, RCC takes the third place in incidence, following prostate
carcinoma and transitional cell carcinoma of bladder.Representing
two percent of the adult malignancies
[1], this malignancy takes the tenth
and fourteenth place among men and women, respectively, with a man to woman
ratio of 3/2 [2]; see Table 1.Table 1
Epidemiologic features of the RCC.
3rd urologic tumor in incidenceMaximum
incidence on 6th decade2% of adults malignanciesMale/Female ratio: 3/285–90% of adult renal parenchymal
malignancies10th male
malignancy and 14th female
malignancy2–6% of child renal malignanciesMore frequent
in afroamerican peopleCancer specific mortality of 40%More frequent
in urban peopleThe
peak incidence occurs in the sixth decade, with 80% of the cases within the 40
to 69-year-old population.Although
the most frequent renal tumor in the childhood is the Wilms tumor, it is
important to state that the RCC represents between 2% to 6% of the renal tumors
in children, without differences between sexes [3, 4].
Besides, the incidence of both malignancies is similar in the second decade of
life. In these early ages the papillary differentiation seems to be more
frequent with higher tendency to present a locally advanced and high-degree
disease at the moment of the diagnosis [5], However, when comparing
stage by stage with adult tumors, we find a better response to surgical
treatment and higher survival rates, even with positive nodal disease.RCC
represents 85 to 90% of renal parenchymal malignancies   [6, 7].Among
urologic tumors, it is the worst in cancer specific mortality, since more than
40% of the patients with RCC die of the disease, opposite to the 20% mortality
observed in prostate cancer or bladder carcinoma.In United States  30 000 new cases are diagnosed every year, and approximately 12 000 patients die
of this disease, with an incidence of near nine cases per 100 000 inhabitants
per year. Afroamericans have 10 to 20% higher incidence, and the reason is not
completely understood [9].Most
of the cases of RCC are sporadic and only 4% are familiar. The estimated number
of new cases in the European Union during 2006 was 63300, with 26400 deaths of
RCC [10]. The estimated survival in 5 years rises to 54% in males and
57% in women [11].Table2 shows different incidences of RCC in the world.Table 2
Geographic distribution of RCC [8].
IncidenceZonesHighDenmark, New Zealand,
Norway,
ScotlandModerateUnited States, Australia, Belgium,
France,
HollandLowSpain, Ireland,
Italy, Japan, Venezuela,
India, ChinaSince
1930 incidence of RCC has been increasing, mostly between 1930 and 1980. Within
this period the incidence also rose from 0.7 to 4.2 per 100 000 per year in
women and from 1.6 to 9.6 in men [12]. Since 1980 a sharp increase has
not been observed comparing to other genitourinary tumors or other type of
malignancies. Similarly, deaths caused by RCC had been stable.Variations
of incidence within the first period could be explained by an easier diagnosis,
as a result of diffusion and routine use of diagnostic tools such as ultrasound
or CT scan, and not due to a real increased incidence of RCC.It is
also important to state that RCC is found incidentally in 1.5% of the autopsies [13].RCC is
more frequent in urban populations rather than in rural ones. This observation
may be explained by the sanitary conditions and the smoking habit in urban
populations. However it has not been related neither to socioeconomic nor to
educational status [14].There
are multiple factors related to the development of RCC; see Table3. Some of them have been
demonstrated in experimental models and in vitro studies, however not all of
them can be considered as definite etiologic factors.Table 3
Some etiologic factors of RCC [15].
Etiologic factorRelative risk
(C.I. 95%)Von Hipple-Lindau
disease100
(not available)Chronic
dialysis32 (not
available)Obesity3.6
(2.3–5.7)Smoking2.3
(1.1–5.1)First
relative with RCC1.6
(1.1–2.4)Hypertension1.4
(1.2–1.7)Dry
cleaners1.4
(1.1–1.7)Diuretics1.3 (1.07–1.52)Trichloroethylene1
(0.7–9.66)Radiation
therapy1.1 (3.2–8.1)Phenacetin1.1
(2.6–6)Polycystic
kidneys0.8
(2–4.5)Cadmium
exposure1 (2–3.9)Arsenic
exposure1.6
(2.3–4.1)Asbestos
exposure1.1 (1.4–1.8)Herein,
we describe these main factors.


### 3.1. Smoking

Multiple
carcinogenic substances have been identified in tobacco and related to a
variety of neoplasms at different levels. A high incidence of RCC in smokers
has been shown [16], estimated in 2.3 fold risk ratio, directly related
with the number of cigarettes and inversely with age of beginning of the habit.
Likewise it has been shown that the carcinogen dimetilnitrosamine induces this
neoplasm in experimental studies. Some authors reported that smokers' risk for
RCC compares to nonsmokers’ after the fifth year of nonsmoking, but a meta-analysis
made by Hunt showed that only after ten years the risk can be similar in both
groups [17], depending on the dose of tobacco inhaled. Another study by
McLaughin [18] and Lipworth [19] confirmed tobacco as the most
important risk factor for renal cancer, detected in 20% of the cases of RCC.But
smoking is not only important in the genesis of RCC, and prognostic nomograms
have also been developed [20]. A multivariate study carried out in
“Miguel Servet” University Hospital of Zaragoza, Spain (in press), smoking
habit increases 2.84 fold (1.27–6,32) the risk of progression of the disease
after surgery [21], similarly to previous studies in other countries.


### 3.2. Chemical Carcinogens

Some radiological
contrasts have been associated with an increased incidence of RCC [22].
Although Cycasin (a substance derived from a palm fruit that grows in the island of Guam) induces RCC in animals, a higher
incidence of this neoplasm within the island population could not be shown.Cadmium
was demonstrated to have influence on the development of RCC in smokers [23, 24].(i)
Asbestos. A significantly
elevated mortality rate for kidney cancer has been reported in two cohort
studies, on insulation workers [25] and on asbestos products workers [26].
Autopsy surveys and animal studies indicate that asbestos fibers can be
deposited in kidney tissue.(ii)
Organic solvents. Pesticides, copper sulphate, benzidine, benzene
herbicides, and vinyl chloride have been found as risk factors of RCC in
prolonged exposure. A dose dependent effect has been seen only for organic
solvents and copper sulphate [27, 28].
Recent
reviews of cohort studies found little or no evidence of an increased risk for
RCC among people exposed to gasoline and petroleum derived products [29, 30].(iii)
Polycyclic
aromatic hydrocarbons. Workers exposed to high levels of
polycyclic aromatic hydrocarbons like coke and coal oven workers, firefighters,
asphalt, and tar have been reported to be at increased risk for kidney cancer.


### 3.3. Radiation

Ionizing
radiation appears to increase the RCC risk slightly, especially among patients
treated for ankylosing spondylitis and cervical cancer [31]. An
increased risk has also been reported for patients receiving radium 224 for
bone tuberculosis and ankylosing spondylitis [32].


### 3.4. Viruses

The
immunosuppressant state related to the HIV infection determines that prevalence
of RCC in the infected population rises 8.5 times compared to the prevalence of
the noninfected ones.The
influence of the polyomavirus SV 40 and of the adenovirus 7 has also been
detected in experimental studies.A
clear-cut association was found between herpes-type virus and renal tumors in
toads. These findings led to search for evidence of herpes virus proteins in
human tumors as well. Although herpes simplex proteins were found in only one
study [33, 34], these findings need to be confirmed by further
research.


### 3.5. Diuretics

This
type of drugs which inhibits water reabsorption on the renal tubule cells seemed
to be responsible for a higher incidence of RCC in patients with chronic intake
of diuretics [35, 36]. Even though, it is noteworthy that
hydrochlorothiazide and furosemide (both effective at the renal tubule level)
induce tubular cell adenomas and adenocarcinomas of the kidney in rats [37].
But Yuan [38] showed in his study that an adequate use of diuretics for
treating hypertension eliminates the risk associated with the above mentioned
drugs, differentiating the influence of hypertension as a risk factor for RCC
rather than diuretics.


### 3.6. Analgesics

This
is a controverted topic. Several studies reported an increased incidence of RCC
in patients with chronic intake of analgesics like paracetamol, salicylates, or
phenacetin [39, 40], however in other studies this relationship has
not been confirmed neither for time of consumption nor for dose of the drug
taken [41].Although
a heavy use of drugs containing phenacetin has been clearly demonstrated to
increase the risk for transitional cancer of the renal pelvis, the association
with RCC is much weaker. On the other hand, an increased risk of RCC associated
with aspirin or acetaminophen consumers was observed [42], but others
believe that neither acetaminophen nor other analgesics have been convincingly
linked with RCC [19].


### 3.7. Oestrogens (dietilestilbestrol)

Although
oestrogens can induce RCC in the animal model, little evidence supports an
association of the disease with oestrogens in humans [43] and only weak
relation has been reported for the use of oestrogens after menopause and for
oral contraceptives [44].


### 3.8. Inheritance

Most
of the cases of RCC are sporadic; however there are some defined types of RCC
with a hereditary pattern [45].(1) Von Hippel-Lindau (VHL) Disease
The
VHL disease is inherited through an autosomal dominant trait. The syndrome is
caused by germline mutations of the VHL tumor suppressor gene, located on
chromosome 3p25-26; these mutations can virtually
always be identified [46]. The VHL protein takes part in cell cycle
regulation and angiogenesis [47]. Patients develop capillary
haemangioblastomas of the central nervous system and retina, clear cell
carcinoma, phaeochromocytoma, pancreatic, and inner ear tumors.
The
clinical diagnostic criteria of VHL disease consist of
(i)
presence of capillary haemangioblastoma in the central nervous system or
retina,(ii)
presence of one of the typical VHL associated extraneural tumors, within
pertinent family history.
Fourty
to sixty percent of the patients with VHL disease present an RCC. Although they
are usually low-grade tumors, the progress rate to metastasis is around 30% [48].
Renal
lesions in carriers of VHL germline mutations are either cysts or clear cell
RCC. They are typically multifocal and bilateral.(2) Hereditary Papillary Renal Carcinoma
This
type of renal carcinoma is an inherited tumor syndrome with autosomal dominant
trait and of late onset, with multiple and bilateral papillary renal cell
carcinomas type 1. The disease is caused by activating mutations of the MET
oncogene which maps the chromosome 7q31.(3) Hereditary Leiomyomatosis and Renal Cell
Carcinoma
This is an autosomal dominant tumor syndrome with germline mutations in
the FH gene (chromosome lq42.3–q43), These patients have the tendency to
acquire benign leiomyomas of the skin and the uterus, and occasionally
papillary renal cell carcinoma type 2 and uterine leiomyosarcomas.(4) Birt-Hogg-Dube Syndrome
This
syndrome is characterized by benign skin tumors, specifically
fibrofolliculomas, trichodiscomas, and acrochordons. Multiple renal tumors and
spontaneous pneumothoraces are also frequent. We can find chromophobe RCC,
typical RCC, hybrid oncocytoma, papillary RCC, or oncocytic tumors.
The
Birt-Hogg-Dube gene maps the chromosome 17p11.2 and encodes the protein called
folliculin. This gene is also involved in sporadic RCC [49].(5) Familiar Clear Cell Renal Cell Carcinoma
These
families present a hereditary form of multiple, bilateral clear cell RCC but
without any clinical evidence of suffering the von Hippel-Lindau disease.
This
hereditary cancer is characterized to present translocations affecting the
chromosome 3. Translocations have been described among the chromosome 3 and the
chromosomes 8 [50], 6 [51, 52], 2 [53, 54], 1 [55],
and 4 [48].


### 3.9. Acquired Cystic Disease/Chronic Dialysis

Approximately
the 35 to 47% of the patients on dialysis and specially those with a very long
history present acquired cystic disease. Some patients with this disease
develop a papillary hyperplasia in the epithelium of the cysts that would be
the origin of the RCC [56, 57].Approximately
the 5 to 9% of the patients with acquired cystic disease will develop an RCC [58],
showing a higher incidence than the general population. As such, we suggest a
close follow-up in the kidney-transplant population, and therefore the
immune-suppressed individuals who are on dialysis for a long time, due to a
high risk of developing RCC.


### 2.10. Diet and Obesity

Hypercaloric
diet and obesity seem to be associated with a higher risk for suffering of RCC. Obesity
accounts for about 30% of renal cancers [19].Some
studies relate a higher incidence of RCC with high body mass index. The
relative risk was found to be 3.3 in males and 2.3 in females [59].The
mechanism of obesity to cause kidney cancer is not clear. Hormonal changes such
as increased levels of endogenous oestrogens in the obese may be the mechanism
through which oestrogens induce renal cancer as observed in animal models.
However, there is scant epidemiologic evidence supporting hormonal
carcinogenesis regarding RCC. Obesity may also predispose to arterionephrosclerosis,
which may render the renal tubules more susceptible to carcinogens. Elevated
cholesterol levels associated with obesity might also play a role, as suggested
by animal studies showing that cholesterol-lowering drugs provide some protection
against RCC. Cholesterol and other lipids may favour tumor development by an
inhibitory effect on immune cells.Low
vitamin D level, which is usually present in obese patients, may predispose to
acquire RCC. This vitamin is known to have inhibitory effects on the growth of
RCC cell lines in vitro [60].Finally,
Lipworth [19] reported that the only consistent protective factor is
consumption of fruit and vegetables.


### 2.11. Coffee, Alcohol, and Other Beverages

Case-control
studies have not confirmed the suggested relationship between kidney cancer and
consumption of coffee, when adjusting the smoking variable. Although two
studies have suggested a positive association, a two-fold increased risk in
both sexes was associated with the use of decaffeinated coffee. In another
study, an increased risk of RCC was found only among women with regular coffee
intake [61]. No dose-dependent risk was reported in either study.On the
other hand, a significant lower risk was reported in Norway
among consumers of seven or
more cups of coffee compared to those who drink two or fewer cups daily,
representing a relative risk of 0.25 [62]. Review studies indicate that
coffee consumption does not increase RCC risk.Few
studies have shown an increased risk of RCC among tea women consumers [63].
Another study has found a dose-response relationship between tea consumption
and kidney cancer mortality [64]. The etiologic significance of these
findings in direct relationship with tea tannins is not clear [65].The
association between alcoholism and kidney cancer mortality has not been
demonstrated by well-deisgned studies [66]. In fact, a recent
case-control study found a statistically significant inverse association
between alcohol consumption and RCC risk [67]. No increase in mortality
from kidney cancer has been reported either within alcoholic patients or
brewery workers [68].


### 2.12. Physical Activity

A
moderate recreational activity reduces the risk of renal cancer both in men and
women. The mechanism is not clear, but there is no doubt that energy expenditure
is one of the major determinants for obesity, which is a strong risk factor for
RCC.


### 2.13. Hypertension

Hypertension
seems to be significant for the development of kidney cancer. The strength of
this relationship is reduced with the use of diuretics and other
antihypertensive drugs, regardless of some of these drugs have been associated
with RCC risk. The main problem consists to identify whether the increased risk
is due to hypertension or antihypertensive medications.Despite
the mechanism for hypertension to cause renal cancer is not completely
understood [69] it seems that
metabolic and/or functional changes in the renal tubular cells produce
carcinogenesis. Wide case-control studies have only found a slight relation
between RCC and hypertension [70]. Further studies are needed.


### 2.14. Alterations in Development of the Kidney

The
anomalous development of the kidneys may act as a teratogenic factor.In
horseshoe kidneys, the area of the isthmus is prone to develop tumors [71],
due to an anomalous migration of the cells toward this area. However, although
the most frequent tumor developed in this malformation is the RCC, the
incidence remains identical to that of the general population, without
differences in evolution or prognosis [72].In conclusion we
can affirm that respect RCC, like in other malignant diseases, ethiology, and
risk factors are not completely understood. There is some evidence that certain
situations, drugs, habits, or genetics are related to the development of renal
cancer, but several studies found controversial results and different degrees
of evidence.Smoking and
obesity seem to be the most important independent risk factors in the genesis
of RCC, reported by different authors.Chromosomal
mutations were clearly identified in the context of well-defined hereditary
diseases.The adequate use
of diuretics and analgesics may be recognized as protective factors not only
for  RCC but for other diseases as well.General healthy
habits like limiting alcohol and coffee intake, decreasing the number of
cigarettes, lowering fat consumption, keeping a suitable weight, and practicing regular exercise may reduce the risk and indicence of RCC.


## 3.1. Smoking

Multiple
carcinogenic substances have been identified in tobacco and related to a
variety of neoplasms at different levels. A high incidence of RCC in smokers
has been shown [16], estimated in 2.3 fold risk ratio, directly related
with the number of cigarettes and inversely with age of beginning of the habit.
Likewise it has been shown that the carcinogen dimetilnitrosamine induces this
neoplasm in experimental studies. Some authors reported that smokers' risk for
RCC compares to nonsmokers’ after the fifth year of nonsmoking, but a meta-analysis
made by Hunt showed that only after ten years the risk can be similar in both
groups [17], depending on the dose of tobacco inhaled. Another study by
McLaughin [18] and Lipworth [19] confirmed tobacco as the most
important risk factor for renal cancer, detected in 20% of the cases of RCC.But
smoking is not only important in the genesis of RCC, and prognostic nomograms
have also been developed [20]. A multivariate study carried out in
“Miguel Servet” University Hospital of Zaragoza, Spain (in press), smoking
habit increases 2.84 fold (1.27–6,32) the risk of progression of the disease
after surgery [21], similarly to previous studies in other countries.


## 3.2. Chemical Carcinogens

Some radiological
contrasts have been associated with an increased incidence of RCC [22].
Although Cycasin (a substance derived from a palm fruit that grows in the island of Guam) induces RCC in animals, a higher
incidence of this neoplasm within the island population could not be shown.Cadmium
was demonstrated to have influence on the development of RCC in smokers [23, 24].(i)
Asbestos. A significantly
elevated mortality rate for kidney cancer has been reported in two cohort
studies, on insulation workers [25] and on asbestos products workers [26].
Autopsy surveys and animal studies indicate that asbestos fibers can be
deposited in kidney tissue.(ii)
Organic solvents. Pesticides, copper sulphate, benzidine, benzene
herbicides, and vinyl chloride have been found as risk factors of RCC in
prolonged exposure. A dose dependent effect has been seen only for organic
solvents and copper sulphate [27, 28].
Recent
reviews of cohort studies found little or no evidence of an increased risk for
RCC among people exposed to gasoline and petroleum derived products [29, 30].(iii)
Polycyclic
aromatic hydrocarbons. Workers exposed to high levels of
polycyclic aromatic hydrocarbons like coke and coal oven workers, firefighters,
asphalt, and tar have been reported to be at increased risk for kidney cancer.


## 3.3. Radiation

Ionizing
radiation appears to increase the RCC risk slightly, especially among patients
treated for ankylosing spondylitis and cervical cancer [31]. An
increased risk has also been reported for patients receiving radium 224 for
bone tuberculosis and ankylosing spondylitis [32].


## 3.4. Viruses

The
immunosuppressant state related to the HIV infection determines that prevalence
of RCC in the infected population rises 8.5 times compared to the prevalence of
the noninfected ones.The
influence of the polyomavirus SV 40 and of the adenovirus 7 has also been
detected in experimental studies.A
clear-cut association was found between herpes-type virus and renal tumors in
toads. These findings led to search for evidence of herpes virus proteins in
human tumors as well. Although herpes simplex proteins were found in only one
study [33, 34], these findings need to be confirmed by further
research.


## 3.5. Diuretics

This
type of drugs which inhibits water reabsorption on the renal tubule cells seemed
to be responsible for a higher incidence of RCC in patients with chronic intake
of diuretics [35, 36]. Even though, it is noteworthy that
hydrochlorothiazide and furosemide (both effective at the renal tubule level)
induce tubular cell adenomas and adenocarcinomas of the kidney in rats [37].
But Yuan [38] showed in his study that an adequate use of diuretics for
treating hypertension eliminates the risk associated with the above mentioned
drugs, differentiating the influence of hypertension as a risk factor for RCC
rather than diuretics.


## 3.6. Analgesics

This
is a controverted topic. Several studies reported an increased incidence of RCC
in patients with chronic intake of analgesics like paracetamol, salicylates, or
phenacetin [39, 40], however in other studies this relationship has
not been confirmed neither for time of consumption nor for dose of the drug
taken [41].Although
a heavy use of drugs containing phenacetin has been clearly demonstrated to
increase the risk for transitional cancer of the renal pelvis, the association
with RCC is much weaker. On the other hand, an increased risk of RCC associated
with aspirin or acetaminophen consumers was observed [42], but others
believe that neither acetaminophen nor other analgesics have been convincingly
linked with RCC [19].


## 3.7. Oestrogens (dietilestilbestrol)

Although
oestrogens can induce RCC in the animal model, little evidence supports an
association of the disease with oestrogens in humans [43] and only weak
relation has been reported for the use of oestrogens after menopause and for
oral contraceptives [44].


## 3.8. Inheritance

Most
of the cases of RCC are sporadic; however there are some defined types of RCC
with a hereditary pattern [45].(1) Von Hippel-Lindau (VHL) Disease
The
VHL disease is inherited through an autosomal dominant trait. The syndrome is
caused by germline mutations of the VHL tumor suppressor gene, located on
chromosome 3p25-26; these mutations can virtually
always be identified [46]. The VHL protein takes part in cell cycle
regulation and angiogenesis [47]. Patients develop capillary
haemangioblastomas of the central nervous system and retina, clear cell
carcinoma, phaeochromocytoma, pancreatic, and inner ear tumors.
The
clinical diagnostic criteria of VHL disease consist of
(i)
presence of capillary haemangioblastoma in the central nervous system or
retina,(ii)
presence of one of the typical VHL associated extraneural tumors, within
pertinent family history.
Fourty
to sixty percent of the patients with VHL disease present an RCC. Although they
are usually low-grade tumors, the progress rate to metastasis is around 30% [48].
Renal
lesions in carriers of VHL germline mutations are either cysts or clear cell
RCC. They are typically multifocal and bilateral.(2) Hereditary Papillary Renal Carcinoma
This
type of renal carcinoma is an inherited tumor syndrome with autosomal dominant
trait and of late onset, with multiple and bilateral papillary renal cell
carcinomas type 1. The disease is caused by activating mutations of the MET
oncogene which maps the chromosome 7q31.(3) Hereditary Leiomyomatosis and Renal Cell
Carcinoma
This is an autosomal dominant tumor syndrome with germline mutations in
the FH gene (chromosome lq42.3–q43), These patients have the tendency to
acquire benign leiomyomas of the skin and the uterus, and occasionally
papillary renal cell carcinoma type 2 and uterine leiomyosarcomas.(4) Birt-Hogg-Dube Syndrome
This
syndrome is characterized by benign skin tumors, specifically
fibrofolliculomas, trichodiscomas, and acrochordons. Multiple renal tumors and
spontaneous pneumothoraces are also frequent. We can find chromophobe RCC,
typical RCC, hybrid oncocytoma, papillary RCC, or oncocytic tumors.
The
Birt-Hogg-Dube gene maps the chromosome 17p11.2 and encodes the protein called
folliculin. This gene is also involved in sporadic RCC [49].(5) Familiar Clear Cell Renal Cell Carcinoma
These
families present a hereditary form of multiple, bilateral clear cell RCC but
without any clinical evidence of suffering the von Hippel-Lindau disease.
This
hereditary cancer is characterized to present translocations affecting the
chromosome 3. Translocations have been described among the chromosome 3 and the
chromosomes 8 [50], 6 [51, 52], 2 [53, 54], 1 [55],
and 4 [48].


## 3.9. Acquired Cystic Disease/Chronic Dialysis

Approximately
the 35 to 47% of the patients on dialysis and specially those with a very long
history present acquired cystic disease. Some patients with this disease
develop a papillary hyperplasia in the epithelium of the cysts that would be
the origin of the RCC [56, 57].Approximately
the 5 to 9% of the patients with acquired cystic disease will develop an RCC [58],
showing a higher incidence than the general population. As such, we suggest a
close follow-up in the kidney-transplant population, and therefore the
immune-suppressed individuals who are on dialysis for a long time, due to a
high risk of developing RCC.


## 2.10. Diet and Obesity

Hypercaloric
diet and obesity seem to be associated with a higher risk for suffering of RCC. Obesity
accounts for about 30% of renal cancers [19].Some
studies relate a higher incidence of RCC with high body mass index. The
relative risk was found to be 3.3 in males and 2.3 in females [59].The
mechanism of obesity to cause kidney cancer is not clear. Hormonal changes such
as increased levels of endogenous oestrogens in the obese may be the mechanism
through which oestrogens induce renal cancer as observed in animal models.
However, there is scant epidemiologic evidence supporting hormonal
carcinogenesis regarding RCC. Obesity may also predispose to arterionephrosclerosis,
which may render the renal tubules more susceptible to carcinogens. Elevated
cholesterol levels associated with obesity might also play a role, as suggested
by animal studies showing that cholesterol-lowering drugs provide some protection
against RCC. Cholesterol and other lipids may favour tumor development by an
inhibitory effect on immune cells.Low
vitamin D level, which is usually present in obese patients, may predispose to
acquire RCC. This vitamin is known to have inhibitory effects on the growth of
RCC cell lines in vitro [60].Finally,
Lipworth [19] reported that the only consistent protective factor is
consumption of fruit and vegetables.


## 2.11. Coffee, Alcohol, and Other Beverages

Case-control
studies have not confirmed the suggested relationship between kidney cancer and
consumption of coffee, when adjusting the smoking variable. Although two
studies have suggested a positive association, a two-fold increased risk in
both sexes was associated with the use of decaffeinated coffee. In another
study, an increased risk of RCC was found only among women with regular coffee
intake [61]. No dose-dependent risk was reported in either study.On the
other hand, a significant lower risk was reported in Norway
among consumers of seven or
more cups of coffee compared to those who drink two or fewer cups daily,
representing a relative risk of 0.25 [62]. Review studies indicate that
coffee consumption does not increase RCC risk.Few
studies have shown an increased risk of RCC among tea women consumers [63].
Another study has found a dose-response relationship between tea consumption
and kidney cancer mortality [64]. The etiologic significance of these
findings in direct relationship with tea tannins is not clear [65].The
association between alcoholism and kidney cancer mortality has not been
demonstrated by well-deisgned studies [66]. In fact, a recent
case-control study found a statistically significant inverse association
between alcohol consumption and RCC risk [67]. No increase in mortality
from kidney cancer has been reported either within alcoholic patients or
brewery workers [68].


## 2.12. Physical Activity

A
moderate recreational activity reduces the risk of renal cancer both in men and
women. The mechanism is not clear, but there is no doubt that energy expenditure
is one of the major determinants for obesity, which is a strong risk factor for
RCC.


## 2.13. Hypertension

Hypertension
seems to be significant for the development of kidney cancer. The strength of
this relationship is reduced with the use of diuretics and other
antihypertensive drugs, regardless of some of these drugs have been associated
with RCC risk. The main problem consists to identify whether the increased risk
is due to hypertension or antihypertensive medications.Despite
the mechanism for hypertension to cause renal cancer is not completely
understood [69] it seems that
metabolic and/or functional changes in the renal tubular cells produce
carcinogenesis. Wide case-control studies have only found a slight relation
between RCC and hypertension [70]. Further studies are needed.


## 2.14. Alterations in Development of the Kidney

The
anomalous development of the kidneys may act as a teratogenic factor.In
horseshoe kidneys, the area of the isthmus is prone to develop tumors [71],
due to an anomalous migration of the cells toward this area. However, although
the most frequent tumor developed in this malformation is the RCC, the
incidence remains identical to that of the general population, without
differences in evolution or prognosis [72].In conclusion we
can affirm that respect RCC, like in other malignant diseases, ethiology, and
risk factors are not completely understood. There is some evidence that certain
situations, drugs, habits, or genetics are related to the development of renal
cancer, but several studies found controversial results and different degrees
of evidence.Smoking and
obesity seem to be the most important independent risk factors in the genesis
of RCC, reported by different authors.Chromosomal
mutations were clearly identified in the context of well-defined hereditary
diseases.The adequate use
of diuretics and analgesics may be recognized as protective factors not only
for  RCC but for other diseases as well.General healthy
habits like limiting alcohol and coffee intake, decreasing the number of
cigarettes, lowering fat consumption, keeping a suitable weight, and practicing regular exercise may reduce the risk and indicence of RCC.



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*Source: 782381-2008-11-04.xml*