epidemiology and risk factors for kidney cancer

nature reviews | urology volume 7 | maY 2010 | 245

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services, 6120 Executive Boulevard, EPS 8100, Bethesda, MD 20892‑7240, USA (W.-H. Chow, l. M. Dong, S. S. Devesa).

Correspondence to: W.‑H. Chow [email protected]

Epidemiology and risk factors for kidney cancerWong-Ho Chow, Linda M. Dong and Susan S. Devesa

Abstract | After more than two decades of rising rates, in recent years the total kidney cancer incidence worldwide has shown signs of stabilizing, or even decreasing. In adults, kidney cancer consists of renal cell carcinoma (RCC), the predominant form, and renal transitional cell carcinoma (RTCC); these types primarily arise in the renal parenchyma and renal pelvis, respectively. Although temporal trends by kidney cancer type are not well established worldwide, incidence of RCC in the US has continued to rise, mainly for early‑stage tumors, while that of RTCC has declined, and total kidney cancer mortality rates have leveled. Stabilization of kidney cancer mortality rates has also been reported in Europe. These trends are consistent with reports of increasing incidental diagnoses and a downward shift in tumor stage and size in clinical series. The changing prevalence of known risk factors for RCC, including cigarette smoking, obesity, and hypertension, is also likely to affect incidence trends, although their relative impact may differ between populations. Accumulating evidence suggests an etiologic role in RCC for physical activity, alcohol consumption, occupational exposure to trichloroethylene, and high parity among women, but further research is needed into the potential causal effects of these factors. Genetic factors and their interaction with environmental exposures are believed to influence risk of developing RCC, but a limited number of studies using candidate‑gene approaches have not produced conclusive results. Large consortium efforts employing genome‑wide scanning technology are underway, which hold promise for novel discoveries in renal carcinogenesis.

Chow, W.‑H. et al. Nat. Rev. Urol. 7, 245–257 (2010); doi:10.1038/nrurol.2010.46

Introductionthe kidney is an essential organ that maintains the homeostatic balance of fluids and solutes in the human body, and removes waste products from the blood. it also helps to regulate blood pressure, and secretes several hor-mones. the kidney is composed of a parenchyma and a collecting system. the parenchyma includes an outer cortex and an inner medulla, and is composed primar-ily of nephrons, functional filtering units consisting of glomeruli and tubules, which are lined by glandular cells. the collecting system includes the renal pelvis and calyces, which are lined by transitional cells.

adult kidney cancers that arise in the renal paren-chyma are mainly adenocarcinomas, also known as renal cell carcinomas (rCCs), while those that arise from the collecting system are mainly transitional cell carci nomas. rCC accounts for more than 90% of adult kidney carci nomas (table 1; surveillance epidemiology and end results [seer] data).1 renal transitional cell carcinoma (rtCC) arises in the renal pelvis, and com-prises less than 10% of histologically confirmed kidney carcinoma. in children, the major type of kidney cancer is nephro blastoma (wilms tumor), which comprises approximately 1.2% of all kidney cancers.

the majority of renal cell adenocarcinoma is of the clear cell subtype, followed by rCC not otherwise speci-fied, papillary, and chromophobe subtypes (table 1). although histologic subtypes of rCC have been shown to differ in clinical features and genetic deter-minants,2,3 epidemiologic data on rCC subtypes are sparse and have not revealed consistent incidence or risk factor patterns.

in this review, we will focus on adult kidney carci-noma, which is comprised of rCC and rtCC, evaluating the descriptive data and risk factor patterns both inter-nationally and in the us. we will conclude by discussing risk factors for development of both rCC and rtCC, including new research involving genetic factors.

Descriptive epidemiologyIncidence patternsthe incidence of rCC varies substantially worldwide (table 2).4 rates are generally high in europe and north america and low in asia and south america, and also vary by country. across europe, rCC rates among males differ more than five-fold, from 2.9 per 100,000 person-years in serbia to 15.2 per 100,000 person-years in the Czech republic. even within a country, rates can vary across regions; for example, within italy, rates of rCC range from 3.6 per 100,000 person years in salerno in the south to 9.0 per 100,000 person years in the north

Competing interestsThe authors declare no competing interests.

foCuS on kIDnEy CAnCEr

nrurol_46_MAY10.indd 245 20/4/10 11:18:26

© 20 Macmillan Publishers Limited. All rights reserved10

mailto:[email protected]

http://www.nature.com/doifinder/10.1038/nrurol.2010.46

246 | MAY 2010 | voluMe 7 www.nature.com/nrurol

east Cancer surveillance network. rCC incidence among females also varies geographically, but the rates are approximately half those among males across all regions. Compared with other european regions, rtCC incidence was not elevated in Croatia and serbia. these countries are located in a region where Balkan nephro-pathy, a chronic interstitial kidney disease known to increase the risk of renal pelvis and ureteral cancers, is endemic.5 Despite this, Balkan nephropathy seems to have a relatively small impact on the overall occurrence of rtCC.

Key points

Kidney cancers among adults arise from the renal parenchyma ■(adenocarcinoma cell type [RCC]) or renal pelvis (renal transitional cell type [RTCC]); RCC is the predominant kidney cancer type

RCC incidence is high in Europe and North America and low in Asia and South ■America; the rarer RTCC generally show less geographic variation

Worldwide, kidney cancer incidence has increased since the late 1970s, until ■the mid‑1990s when it leveled or declined in many countries

In the US, RTCC incidence has decreased while RCC incidence has increased ■—much of this rise is due to the increasing diagnosis of early‑stage tumors

Cigarette smoking, obesity and hypertension are well‑established risk factors ■for RCC

Genetic factors might also influence RCC risk; ongoing large consortium ■studies promise to identify novel etiologic and prognostic factors for RCC

in the us, rCC incidence differs among racial and ethnic populations (table 2).4 rates are lowest among populations of asian or Pacific island descent, mirror-ing the rates of their countries of origin. the rCC rates among white Hispanics in the us are, however, much higher than those reported in latin america, suggest-ing that environmental exposure could have a role in the development of the disease.

in general, rtCC incidence rates are much lower than those for rCC (table 2). there are no clear regional differ ences in incidence patterns, although the rates seem to be lowest in latin america. men in certain countries, such as Japan (Hiroshima) and the Czech republic, seem to have a particularly high rtCC incidence, but the reason is unclear. in the us, rtCC incidence among non- Hispanic white individuals is higher than among the other racial and ethnic groups, including white Hispanics. male:female rate ratios for rtCC also vary between populations, being 2:1 or lower in the majority of countries. this male:female 2:1 ratio contrasts with the ratio of almost 4:1 for bladder cancer,6 a tumor that is also mostly of transitional cell type and thought to share common risk factors with renal pelvis cancer. this observa tion suggests that these two malignancies might have diverse etiologies.

Temporal trendsData that allow the separate evaluation of rCC and rtCC trends internationally are limited, as until recently most registries did not report histologic type-specific data.7,8 on the basis of the us experience, histologic data are necessary to accurately classify kidney carcinoma as rCC or rtCC.9 if only anatomic site codes are used, as many as 17% of rtCC cases reported to the seer regi stries would be classified as renal parenchyma cancer or kidney cancer not otherwise specified, rather than as renal pelvis cancer.

in general, total kidney cancer incidence rose from the 1970s until the mid-1990s, when it leveled or dropped in many registries. this pattern is particularly noticeable across europe, as illustrated by selected regis tries shown in Figure 1.4,10 leveling of kidney cancer incidence is also shown in registries in other regions, including north america (Canada: alberta, British Columbia; us: seer white and black males), oceania (new Zealand; australia: new south wales females), and asia (China: Hong Kong; singapore: Chinese males; Japan: Hiroshima females).4,10 this decline in incidence seems to have started earlier in some countries, including Canada, sweden, and Hong Kong. this leveling of kidney cancer incidence was consistent with patterns reported in other european countries, such as Finland, Denmark, and slovenia.8

in the us, the incidence of total kidney cancer diag-nosed between 1978 and 2002 (Figure 1), and specifically of rCC diagnosed between 1977 and 2006 (Figure 2), has risen consistently over time, with larger and more-rapid increases among the black than white population. rates of rtCC in the us, however, have leveled or even declined.

limited reports from cancer registries that pro-vided long-term incidence data separately for rCC and

Table 1 | Kidney cancer incidence by type, 2002–2006

Type of disease (ICD-o-3 morphology codes) Cases %

Total kidney cancer (including renal pelvis) 17,037 100.0

Of which*

Not microscopically confirmed 1,668 9.8

Microscopically confirmed 15,369 90.2

Of which‡

Ill‑defined (8000–8046) 194 1.3

Nephroblastoma (Wilms tumor; 8960) 181 1.2

Sarcomas, other (8800–9540; except 8960) 97 0.6

Carcinomas (8050–8575) 14,897 96.9

Of which§

Transitional cell/squamous cell (RTCC; 8050–8130 [renal pelvis]) 1,246 8.40

Adenocarcinoma (RCC; (8140–8575 [renal parenchyma]) 13,651 91.60

Of which||

RCC, not otherwise specified (8312) 3,614 26.5

Clear cell (8310) 6,819 50.0

Papillary (8260) 1,457 10.7

Chromophobe (8270, 8317) 670 4.9

Other¶ 1,091 8.0

Histologic type was based on data reported to SEER, without standardized review; data are taken from the US SEER 9 registries for white and black populations. Adenocarcinoma designation includes all adenocarcinomas occurring in the renal pelvis (0.1%) as well as ‘kidney, not otherwise specified’ (99.9%). Transitional cell/squamous cell designation includes all transitional cell carcinomas (97.7%) and squamous cell carcinoma (2.3%) coded to kidney or renal pelvis. *Proportion of total kidney cancer (renal parenchyma, renal pelvis, sarcomas, nephroblastoma, ill‑defined type). ‡Proportion of pathologically confirmed disease. §Proportion of pathologically confirmed kidney and renal pelvis carcinomas. ||Proportion of pathologically confirmed adenocarcinoma. ¶Includes mixed cell types, adenocarcinoma not otherwise specified, and other rarer adenocarcinomas. Abbreviations: RCC, renal cell carcinoma; RTCC, renal transitional cell carcinoma; ICD, International Classification of Diseases; SEER, Surveillance, Epidemiology, and End Results.1

rEVIEWS

nrurol_46_MAY10.indd 246 20/4/10 11:18:26



rtCC12,13 support the us seer data. incidence rates for rCC in Connecticut (whic has the oldest us cancer registry) increased consistently between 1935 and 1989, while rates for rtCC also increased until the 1970s, when they plateaued.12 a recent report from Denmark showed that kidney cancer incidence rates (including renal pelvis cancer) rose between 1944 and 1973, after which they leveled. Compared with overall kidney cancer incidence, increases in renal pelvis and ureteral cancers were more-substantial between 1944 and 1988, after which rates started to fall.13 this report did not, however, use histol-ogy to classify renal carcinoma subtype, which could lead to an underestimation of rtCC incidence.

in contemporary practice, cases of rCC are being diagnosed at an earlier stage, and a general shift has similarly occurred towards smaller tumor size at diag-nosis among stage i (localized) tumors.14 incidental diagnoses of small tumors have also been documented and are attributed to the widespread use of abdominal imaging procedures for diagnostic work-up, in most cases probably to examine other abdominal disorders.15 the stage-specific trends in rCC incidence in the us support the observation that rCC is being diagnosed at an earlier stage, with marked increases in incidence over time seen only in tumors that were localized at diagnosis (Figure 3).11 when tumor size was examined, the rate of

Table 2 | International kidney cancer incidence 1998–2002

Population renal cell carcinoma* renal transitional cell carcinoma‡

Male female Male:female ratio Male female Male:female ratio

North America

USA, SEER 14: Asian/Pacific Islander 4.7 2.2 2.1 0.5 0.2 2.5

Canada, British Columbia 6.5 3.2 2.0 0.6 0.3 2.0

Canada, Alberta 9.1 5.1 1.8 0.6 0.4 1.5

USA, SEER 14: white Hispanic 9.7 5.2 1.9 0.6 0.3 2.0

USA, SEER 14: white non‑Hispanic 10.0 4.8 2.1 0.8 0.4 2.0

USA, SEER 14: black 11.5 5.7 2.0 0.5 0.3 1.7

Asia

Korea, Incheon 2.8 1.2 2.3 0.7 0.2 3.5

China, Hong Kong 2.9 1.5 1.9 0.3 0.1 3.0

Singapore, Chinese population 3.8 1.8 2.1 0.5 0.2 2.5

Japan, Hiroshima§ 5.8 1.7 3.4 1.3 0.5 2.6

Europe

Serbia 2.9 1.5 1.9 0.8 0.6 1.3

Italy, Salerno 3.6 1.6 2.3 0.8 0.2 4.0

Croatia 3.9 1.7 2.3 0.3 0.2 1.5

Spain, Zaragoza 4.7 2.3 2.0 0.7 0.1 7.0

Sweden 6.0 3.6 1.7 0.7 0.4 1.8

The Netherlands, Eindhoven 6.0 3.3 1.8 0.7 0.4 1.8

UK, Northern England 6.6 3.4 1.9 0.8 0.4 2.0

Italy, North East Network 9.0 3.9 2.3 0.7 0.3 2.3

Slovak Republic 9.1 4.4 2.1 0.7 0.5 1.4

Germany, Munich 9.7 4.4 2.2 0.7 0.5 1.4

Czech Republic 15.3 7.2 2.1 1.0 0.6 1.7

Oceania

New Zealand 6.5 3.4 1.9 0.5 0.3 1.7

Australia, New South Wales 9.0 4.3 2.1 0.8 0.9 0.9

Latin America

Costa Rica 2.5 1.4 1.8 0.2 0.1 2.0

Brazil, Sao Paulo 4.2 1.9 2.2 0.1 0.1 1.0

Incidence rates per 100,000 person years, age‑standardized to world population, by cancer subtype and gender (1998–2002), microscopically verified cases only. Registries were selected if cancer was reportable by legislation or administrative order, >70% of cases had pathologic confirmation, and a relatively low proportion of cases treated outside registration area or nonresidents treated inside registration area. *Includes all adenocarcinomas occurring in kidney and renal pelvis, based on the IARC classification. ‡Includes transitional cell carcinoma and squamous cell carcinoma occurring in kidney and renal pelvis. §Year of diagnosis 1996–2000. Extracted from Cancer Incidence in Five Continents, Volume IX4 Abbreviations: IARC, International Agency for Research on Cancer; SEER 14, Surveillance, Epidemiology, and End Results program 14 registries: the 7 states of Connecticut, Iowa, New Mexico, Utah, Kentucky, New Jersey, and Louisiana, and the 7 areas of Greater San Francisco (San Francisco–Oakland and San Jose–Monterey, California), Los Angeles (California), Greater California (California excluding SF/SJM/LA), Detroit (Michigan), Seattle–Puget Sound (Washington), and Atlanta plus Rural Georgia (Georgia).


nrurol_46_MAY10.indd 247 20/4/10 11:18:27



increase in the incidence of tumors <2.0 cm far outpaced that of tumors of larger sizes.16 more-modest increases in incidence, however, were also observed for tumors of larger size, while the incidence of tumors of undeter-mined size declined, again probably due to improved diagnostic work-up and documentation of tumor size. the diagnosis of rCC at an increasingly early stage and small size might have contributed to the recent leveling of kidney cancer mortal ity rates in the us (Figure 2b)17 and many countries in europe.8 us seer registry data, however, show that survival of patients with rCC across all disease stages has improved over time, suggesting a general improvement in early detection and management of these patients.16

Risk factorsrenal transitional cell carcinomaBecause of its rarity, rtCC has not been examined exten-sively in epidemiologic studies. information on risk factors for rtCC is derived mainly from case–control

studies conducted during the 1980s and early 1990s,18 in which the exposure to risk factors of patients diagnosed with rtCC was compared with an equivalent group of control subjects without cancer. in general, cases in these studies were defined by cancer anatomic site rather than morphologic classifications. Data from these studies, along with further clinical and laboratory data, provided convincing evidence that cigarette smoking and use of phenacetin-containing analgesics increase the risk of developing rtCC.18–21 in two of the largest case–control studies on renal pelvis cancer, smokers were reported to have an elevated risk of double or triple that among nonsmokers, and the risk among current smokers was approximately twice as high as in former smokers.22,23 this risk further increased with increasing number of cigarettes smoked and years of smoking, and was reduced with years of smoking cessation.

analgesic mixtures containing phenacetin have been classified by the international agency for research on Cancer (iarC) as a Group 1 carcinogen, with sufficient

30 –

10 –

1 –

Americas

USA, SEER 9, black

USA, SEER 9, white

Canada, Alberta

Canada, British Columbia

Columbia, Cali

Costa Rica

Mal

es: in

cide

nce

per

10

0,0

00

per

son-

year

s

Czech Republic

Slovak Republic

The Netherlands, Eindhoven

Sweden

Spain, Zaragoza

Australia, New South Wales

New Zealand

Japan, Hiroshima City

Singapore, Chinese

China, Hong Kong

30 –

10 –

1 –

30 –

10 –

1 –

30 –

10 –

1 –

Europe Oceania Asia

30 –

10 –

1 –

1980 1990 2000 2010

Year of diagnosis

Americas

Fem

ales

: in

cide

nce

per

10

0,0

00

per

son-

year

s 30 –

10 –

1 –

30 –

10 –

1 –

30 –

10 –

1 –

1980 1990 2000 2010

Year of diagnosis

Europe

1980 1990 2000 2010

Year of diagnosis

Oceania

1980 1990 2000 2010

Year of diagnosis

Asia

Figure 1 | International total kidney cancer incidence from 1978–1982 to 1998–2002. Rates per 100,000 person‑years, age‑adjusted to the world standard, by gender, continent, and country.

rEVIEWS

nrurol_46_MAY10.indd 248 20/4/10 11:18:28



Figure 2 | US kidney cancer rates from 1977–1981 to 2002–2006. Rates per 100,000 person‑years, age‑adjusted to the US 2000 population, by race and gender. a | SEER 9 incidence by kidney type, microscopically verified cases only. b | US total kidney cancer mortality.

20 –

10 –

1 –

0.1 –

1980 1990 2000 2010

Year of diagnosis

White males

Localized

Inci

denc

e pe

r 100,0

00

per

son-

year

s

20 –

10 –

1 –

0.1 –

1980 1990 2000 2010

Year of diagnosis

White females 20 –

10 –

1 –

0.1 –

1980 1990 2000 2010

Year of diagnosis

Black males 20 –

10 –

1 –

0.1 –

1980 1990 2000 2010

Year of diagnosis

Black females

Regional Distant Unstaged

Figure 3 | US SEER 9 renal cell carcinoma incidence from 1977–1981 to 2002–2006. Rates per 100,000 person‑years, age‑adjusted to the US 2000 population, by race, gender, and stage at diagnosis; microscopically verified cases only.

20 –

10 –

1 –

0.1 –

1980 1990 2000 2010

Year of diagnosis

Males

White RCC

Black RCC

White RTCC

Black RTCC

Inci

denc

e pe

r 1

00

,00

0 p

erso

n-ye

ars

a

White male

Black male

White female

Black female

20 –

10 –

1 –

0.1 –

1980 1990 2000 2010

Year of death

b20 –

10 –

1 –

0.1 –

1980 1990 2000 2010

Year of diagnosis

Females

Mor

talit

y pe

r 100,0

00 p

erso

n-ye

ars


nrurol_46_MAY10.indd 249 20/4/10 11:18:30



evidence for an increased risk of urothelial carcinoma in humans.20 Phenacetin alone was classified as a Group 2a probable carcinogen, because exclusive use of phenacetin in humans was uncommon, making it difficult to separate the effect of phenacetin from that of other active ingredients in a formula, as well as from the use of other analgesic preparations. since the late 1960s, phenacetin use has been phased out in most industrial-ized countries, and it was eventually banned from most worldwide markets in the late 1970s to mid-1980s. acetaminophen (paracetamol) is a primary metab-olite of phenacetin.24 Heavy use of this drug has been linked to end-stage renal disease and rtCC in case–control studies, but the evidence is inconclusive.18,25 a population- based cohort study of acetaminophen users in Denmark based on linkage of prescription database and cancer registry incidence data reported a non-significant increase in risk of developing combined renal pelvis–ureteral cancers.26 recent reports indicate a sub-stantial decline in the prevalence of analgesic nephro-pathy among autopsy subjects between 1980 and 2000,27 and no evidence of analgesic nephropathy in patients with end-stage renal disease who had high use of non-phenacetin analgesics.28 these observations, therefore, do not support a role for non-phenacetin analgesics in the development of end-stage renal disease and related risk of developing rtCC.

an increased occurrence of urothelial carcinoma, including rtCC, has been observed among patients with a rapidly progressive form of nephropathy after inges-tion of a Chinese nephrotoxic herb contaminant.29 this form of nephropathy has a pattern of interstitial fibrosis similar to that of Balkan endemic nephropathy, a known

risk factor for renal pelvis cancer.5,7 ecologic studies have linked high levels of arsenic in drinking water to kidney cancer mortality.30–32 studies of cancer incidence using histologic data have shown that the increased incidence of kidney cancer was mainly due to rtCC.33,34 ecologic studies conducted in low-exposure areas, however, have detected no increase in kidney cancer incidence or mortal ity,35–38 although a link with kidney diseases has been reported.36

other risk factors, including hypertension and kidney and ureteral stones, have been suggested, but their associa tions with rtCC development have not been demonstrated consistently.39–41 Data on Bmi and dietary practices are limited for rtCC and do not suggest any association.18,41,42 equally inconclusive are data linking risk of rtCC development to occupation, based on a small number of studies.18,43

renal cell carcinomaDespite the proximity in anatomic site of origin, risk factors for development of rCC are generally differ-ent from those for rtCC. an exception is cigarette smoking, which is an established risk factor for both tumor types. a number of predisposing conditions, including obesity and hypertension, are known to increase the risk of rCC development (table 3). an ele-vated rCC risk has also been observed for individuals with a history of diabetes mellitus, but the effect of this disease is difficult to separate from that of obesity and hypertension. evidence is also accumulating, although not yet conclusive, to suggest an association between development of rCC and other factors, such as physical activity, alcohol consumption, occupational exposure

Table 3 | Risk factors for renal cell carcinoma

risk factors Association with rCC Comment

Established*

Cigarette smoking Positive Dose–response association with pack‑yearsSmoking cessation reduces risk

Excess body weight Positive Dose–response association with usual adult BMIEffect of weight change on risk unclear

Hypertension Positive Dose–response association with blood pressureControl of hypertension might reduce RCC riskEffect independent of body weight

Familial cancer syndromes Positive Inherited RCC in affected families

Suspected‡

Diabetes mellitus Positive Effect independent of obesity and hypertension not yet established

End‑stage renal disease Positive Increased subsequent RCC risk

Parity in women Positive Dose–response association with number of birthsPossible inverse association with age at first birth

Physical activity Inverse Dose–response association with activity level

Alcohol consumption Inverse Dose–response association with quantity consumed

Trichloroethylene exposure Positive Dose–response association with exposure level

Genetic predisposition Positive Positive association with a family history of kidney cancerIncreased risk of sporadic RCC in genetically susceptible individuals

*Observed in nearly all studies; exposure precedes RCC; dose–response relationship; risk reduction with removal of exposure. ‡Observed in numerous studies, but results conflicting; exposure precedes RCC; dose–response relationship; effect independent of known risk factors not established; small number of exposed RCC cases; confounding by heightened clinical surveillance possible; exposure assessment incomplete. Abbreviation: RCC, renal cell carcinoma.

rEVIEWS

nrurol_46_MAY10.indd 250 20/4/10 11:18:30



to trichloroethylene, and parity in women. most of the initial leads to these suggested risk factors have been provided by case–control studies,18 and results from cohort studies are increasingly being published as sufficient numbers of patients with rCC are accumu-lated. as the exposure data and biological samples for molecular analyses in cohort studies are collected before cancer diagnosis, results from these investigations are less prone to recall bias and are unaffected by the cancer and its treatment. when possible, this review of rCC risk factors draws on recent results from cohort studies and pooled analyses. some results from case–control studies also are included when they are complementary to the cohort results.

Cigarette smokingCigarette smoking is considered a causal risk factor for rCC by the iarC and the us surgeon General.21,44 Compared with people who have never smoked, the risk of developing rCC is increased by approximately 50% in male and 20% in female smokers.45 a clear dose–response pattern of risk was observed with increasing number of cigarettes smoked. smoking cessation allevi-ates this risk, but only among long-term quitters of 10 or more years.16,45 the overall prevalence of cigarette smoking in developed countries has declined over time, while it has remained stable or increased in developing countries.46 For example, the total annual consumption of manufactured cigarettes peaked in 1963 in the us, 1976 in Denmark, 1985 in italy, and 1980 in australia.47 these patterns suggest that the relative importance of cigarette smoking in the development of kidney cancer might rise in developing countries, while declining in developed regions.

Cigarette smoking is hypothesized to increase the risk of rCC through chronic tissue hypoxia resulting from carbon monoxide exposure, and via smoking-related dis-orders such as chronic obstructive pulmonary disease.48 in addition, peripheral blood lymphocyte samples from patients with rCC showed greater Dna damage than samples from control participants after treatment with a tobacco-specific N-nitrosamine (nnKoac), and rCC risk increased with increasing levels of Dna damage in the nnKoac-treated lympho cytes in a case–control comparison after adjusting for differences in smoking status and other confounding factors.49 these observa-tions suggest that increased sensi tivity to nicotine-derived nitrosamine ketone (nnK) in cigarette smoke may predispose susceptible individuals to elevated rCC risk. Deletions in chromo some 3p, a frequent site of genetic alterations in rCC, were also more common in cultured peripheral blood lymphocyte cells from patients with rCC than in those from control subjects after the cells from both groups were treated with benzo[α]pyrene diol epoxide (BPDe), a metabolic product of the major cigarette smoke constituent benzo[α]pyrene.50 these data suggest that BPDe sensitivity in chromosome 3p may reflect genetic susceptibility to rCC, and that exposure to tobacco smoke might increase rCC risk in susceptible individuals.

Obesityexcess body weight was estimated to have a role in the development of more than 40% of rCC cases in the us, and more than 30% in europe, based on estimates of rCC risk associated with overweight and obesity, and the prevalence of these conditions among us and european populations during the 1980s and 1990s.51 Prospective studies conducted worldwide found that individuals who were overweight or obese at baseline had an increased risk of subsequent rCC, in a dose–response manner,52–55 by 24% for men and 34% for women for every 5 kg/m2 increase in Bmi.56 waist-to-hip ratio, weight cycling, and weight gain during adult-hood have also been associated with increased risk of rCC, but their impact is difficult to disentangle from the effects of Bmi.16

the prevalence of obesity has increased markedly, not only in high-resource regions, such as the us and western europe, but also in low-income and middle-income countries.57 Comparable long-term international data on obesity prevalence are limited,58 although it has been reported that the rise in overweight and obesity seems to be faster in lower income countries since the 1970s.59 in the us, the age-adjusted prevalence of obesity has not increased significantly among women since 1999, and among men since 2003.60 the global rise in obesity is likely to have contributed to the increase in rCC inci-dence. However, it is probably too soon for the recent stabilizing obesity prevalence in high-resource coun-tries to have had a substantial impact on current rCC trends, given the long latent period of cancer develop-ment. several mechanisms might explain the increased risk of rCC development in obese individuals. these mechanisms include chronic tissue hypoxia, insulin resistance and compensatory hyperinsulinemia, altered endocrine milieu and production of adipokines, obesity-induced inflammatory response, and lipid peroxidation and oxidative stress; however, direct evidence for these mechanisms in humans is limited.61

HypertensionHypertension is a major chronic disease with increasing prevalence, which affects approximately 20–40% of the world’s population.62,63 uncontrolled hyper tension can lead to chronic kidney disease, worsening renal function, and enhancing progression to end-stage renal disease, conditions that may predispose to the development of rCC. the extent to which the rising prevalence of hypertension might have contributed to increasing rates of rCC is difficult to estimate, owing to differences between populations in the awareness and effectiveness of hypertension control and other contributing risk or protective factors.

although uncommon, cancer cells in some rCCs can produce renin, leading to hypertension through its effect on the renin–angiotensin system, which has a central role in blood pressure regulation.64 Hypertension has also been reported in a small percentage of patients with advanced rCC treated with sorafenib, a potent angiogenesis inhibitor.65


nrurol_46_MAY10.indd 251 20/4/10 11:18:30



sufficient evidence exists to demonstrate that hyper-tension predisposes to development of rCC. a number of studies have reported an association between develop-ment of rCC and a history of long-term hypertension, and cohort studies with blood pressure measurements taken at baseline generally report a dose–response associa tion of increasing rCC risk with rising blood pressure.41,66–68 users of diuretics and other anti-hypertensive medications also have an elevated risk of rCC, but an effect of these agents independent from that of hypertension per se has not been established.68–72 in a swedish cohort study with sequential blood pressure measurements, rCC risk increased with elevation of blood pressure and decreased with reduction in blood pressure over time,41 indicating a tumor-promoting effect of hyper tension, and that effective control of blood pressure might reduce rCC risk.

Despite the strong relationship between obesity and hypertension, these disorders seem to be independently associated with risk of rCC. rCC risk is higher among individuals who are both obese and hyper tensive than among patients who have only one of these dis orders.41,68,71 the biological mechanisms underlying the association between hypertension and rCC are unclear, but might include chronic renal hypoxia and lipid peroxidation with formation of reactive oxygen species.48,73

Other pre-existing disordersa history of diabetes mellitus has been linked to an increased risk of developing rCC in cohort studies, but a role independent from those of obesity and hyper-tension has not been conclusively demonstrated.66,69,71,74 the associa tion between elevated rCC risk and diabetes history was not significant after adjustment for hyper-tension and Bmi in some studies;66,69,71 another study inadequately adjusted for the effect of hypertension and is, therefore, inconclusive.74

an increased risk of rCC has been reported in patients with end-stage renal disease who are on long-term hemo-dialysis, as well as after renal transplantation.75,76 Kidney transplant recipients are also more likely to have subse-quent rCC diagnosed in the native kidney than in the transplanted kidney.77

evidence suggests an increased risk of rCC in patients with acquired renal cystic disease.78 an elevated risk of primary rCC has also been reported among cancer survi-vors,79 and in one study the risk of metachronous bi lateral rCC increased steadily with younger age at diagnosis of the first cancer.80 the heightened clinical surveillance in these patient groups, however, might contribute to the more-frequent diagnosis of a subsequent rCC.

Reproductive and hormonal factorsan increased risk of rCC has been associated with increasing parity among women in several cohort studies,81–84 although not all studies support this observa-tion.85 Compared with nulliparous women, rCC risk increased 40–90% among women who had given birth,81,82,84 and rose with increasing number of births.81–84 an inverse association with maternal age at first birth has

also been reported, with the highest risk among women who had four or more births before the age of 26 years.84 the mechanisms underlying this observed association of rCC with parity are unclear, although pregnancy-induced hypertension and renal stress might have a role. associations of rCC with other reproductive factors, including the use of oral contraceptives and hormone replacement therapy, are not consistently observed.16

Physical activityregular physical activity is associated with a reduced risk of several types of cancer, particularly colon and breast cancers.86 Data linking physical activity to rCC risk are still limited, but most studies examining this issue have reported a lowering of risk with higher level of physi-cal activity.66,71,87–89 several cohort studies have reported a dose–response pattern of reduction in rCC risk with increasing levels of activity, assessed by current exercise, routine physical activity, recreational activity, or energy expenditure in a typical day.71,88,89 Physical activity has been shown to reduce body weight and blood pres-sure, improve insulin sensitivity, and reduce chronic inflamma tion and oxidative stress;86,90–92 all these changes could contribute to a reduction in rCC risk.

Dietnutrition is an important determinant of growth, body function, and immune defense. overconsumption or deficiency in certain dietary constituents has been linked to a variety of diseases, including cancer.57 Diets rich in fruits and vegetables were associated with a low risk of rCC in a pooled analysis of cohort studies,93 but the reported association of antioxidant nutrients such as vita-mins a, C and e, and carotenoids with the disease is vari-able.94–97 although high consumption of fat and protein, particularly of animal origin, is a potential risk factor, a pooled analysis of cohort studies and the results from a large multicenter european cohort study revealed no association between intake of these macronutrients and rCC in multivariate models.98–100 the role of processed meat, however, might warrant further investiga tion, as a weak association with rCC was observed among individuals with the highest intake (≥27 g/day), even after adjustment for known rCC risk factors.98,100 self-reported dietary caloric consumption is not associated with rCC risk;99,101 however, a positive association was observed with rCC once potential systematic bias in self-reported caloric intake was removed by calibration using a doubly-labeled water protocol. the inclusion of Bmi in the dietary model reduced the association with caloric intake to a nonsignificant level, indicating that these two factors are highly correlated.101 this observa tion further suggests that evaluation of cancer risk should consider the overall picture of energy balance, encompassing both energy intake and output through physical activity, as well as Bmi.

the chemical acrylamide is used in producing glues, paper and cosmetics, and to produce poly acrylamide, which is used in the treatment of drinking and waste water. acrylamide is naturally produced when starch-rich

rEVIEWS

nrurol_46_MAY10.indd 252 20/4/10 11:18:30



food is cooked at high temperatures. it is classi fied by the iarC as a probable human carcinogen,102 and has been detected at unexpectedly high levels in common fried and baked foods.103 epidemiologic studies assess-ing the link between acrylamide and rCC risk, however, have yielded mixed results.16,104 two case–control studies in sweden found no association with rCC, with risk estimates of 1.0–1.1 (odds ratio [highest versus lowest quartile]).105,106 By contrast, a study in a Dutch cohort reported a statistically significant 60% increase in risk among indivi duals in the highest quintile of acrylamide intake (mean 40.8 μg/day) compared with those in the lowest quintile (mean 9.5 μg/day).107 Given the ubiquity of acrylamide in foods, monitoring its carcinogenic potential in humans through existing studies might be prudent.

alcohol consumption has been inversely associated with rCC risk in a dose–response manner in prospective studies, with an estimated 28% reduction in risk among individuals who consumed at least 15 g of alcohol—equivalent to slightly more than one alcoholic drink—per day.108 this inverse association was observed for all types of alcoholic beverage, including beer, wine, and spirits. By contrast, no association was found between rCC and total fluid intake from all beverages or individual types of beverage, including coffee, tea, milk, juice, soda, and water.109

Occupation and environmentrCC is not generally considered an occupational disease, but associations with certain occupations and related exposure to some industrial agents have been reported. trichloroethylene (tCe), considered a probable human carcinogen by the iarC,110 is by far the most extensively examined chemical in relation to rCC risk. widely used as a metal degreaser and chemical additive, tCe has also become a common environmental contaminant.111 epidemiologic evidence linking tCe to rCC is accu-mulating, with a large number of studies reporting an increase in risk with increasing levels of exposure.112,113 this association has been found using a variety of study designs and exposure-assessment methods, in different

populations and various settings. the observation of this finding across diverse studies increases the likelihood of a true association. the difficulties in determining the mode of action and the complexities of tCe pharmaco-kinetics, co-exposure to other solvents, and various other study limitations, such as small number of exposed sub-jects and inadequate adjustment for confounding factors, however, have precluded the establishment of a causal association to date.111–114

at high levels of exposure, heavy metals such as cadmium, lead, and arsenic are known to be nephrotoxic. environmental exposure to low levels of these metals, as measured by blood and urine markers, has also been associated with hypertension and indicators of kidney disease.115–118 studies of occupations that may have expo-sure to these agents, such as metal workers, printers, and oil refinery workers, have suggested associations with rCC risk, but these associations have not been consis-tently observed.16,18 such studies that are based only on job title and industry of employment are limited by the lack of specific exposure information.

Genetic susceptibilityinherited rCC is known to occur in a number of familial cancer syndromes, most notably in von Hippel–lindau (vHl) disease. this disease is characterized by altera-tions in the VHL gene and predisposition to a number of disorders among family members, including the clear cell subtype of rCC.119 only a very small proportion of patients with rCC are from families with these rare syndromes, although the exact frequency is difficult to pinpoint. a familial predisposition has, however, been demonstrated in sporadic cases of rCC; a recent meta-analysis demonstrated that the risk of rCC was more than doubled among individuals who had a first-degree relative diagnosed with kidney cancer.120 the interplay between exposure to environmental risk factors and the genetic susceptibility of exposed individuals is believed to influence the risk of developing sporadic rCC. studies of signature tumor Dna alterations may provide clues to relevant environmental carcinogen exposures.121 VHL mutations in rCC have previously been linked to heavy

Table 4 | Genetic variants associated with renal cell carcinoma risk: suggestive evidence*

Pathway gene Main effect‡ no. of studies

gene association and interaction with rCC risk

Xenobiotic metabolism GSTM1 Null§ 7 Significant interaction with pesticide exposure; inconsistent interaction with TCE

Xenobiotic metabolism GSTT1 Null 6 Significant interaction with pesticides and cruciferous vegetables

Xenobiotic metabolism NAT2 Null 3 Significant interaction with smoking

Vitamin D receptor pathway VDR Increased risk

3 Comprehensive analysis identified 5 significant SNPs out of 29 studied; inconsistent results for RFL polymorphisms

Lipid peroxidation APOE-C1 Increased risk

2 Comprehensive analysis identified 3 significant SNPs out of 5 studied; comprehensive analysis identified 1 significant region in promoter; 2 of the 3 significant SNPs (rs405509, rs8106822) replicated in a second study population

*Suggestive evidence refers to at least 2 studies evaluating and demonstrating an association for a variant in that gene. ‡Refers to published associations either comparing the homozygous variant group, or the combined heterozygous plus homozygous variant, to the reference group. §Refers to no association being found. Abbreviations: RCC, renal cell carcinoma; SNP, single nucleotide polymorphism; TCE, trichloroethylene.


nrurol_46_MAY10.indd 253 20/4/10 11:18:30



tCe exposure,122 but this finding has yet to be replicated in other occupational studies;123 recent advances in tumor array technology and high throughput scanning and sequencing techniques will potentially enhance the opportunities for such discoveries.124,125

a 2003 study demonstrated shorter telomere length in peripheral blood lymphocyte Dna in patients with rCC compared with control subjects, an association that seemed to be modified by cigarette smoking.126 shortened telomeres might lead to chromosomal abnormali ties and serve as one of the initiating steps in carcino genesis; this study was the first to demonstrate a relationship between telomere dysfunction and rCC risk. another study indicated that low mitochondrial Dna (mtDna) content in peripheral blood lymphocytes was associated with elevated risk of rCC in a dose–response manner.127 although lymphocyte mtDna content was significantly lower among smokers than nonsmokers in this study, smoking did not modify the association between mtDna and rCC risk. Both telomere length and mtDna content may potentially assist in understanding rCC carcino-genesis, but findings from both the above studies have yet to be confirmed, preferably in larger studies with prospectively collected genomic Dna samples.

rCC risk has been evaluated in relation to a number of common genetic variants in leukocyte Dna (tables 4 and 5). most studies to date have identified a few genes in a pathway that might be relevant for renal carcino-genesis, and then used a candidate-gene approach to find single nucleotide polymorphisms (snPs) associated with disease.16 most promising results have yet to be replicated in further investigations.

Genes encoding the glutathione S-transferase (Gst) enzymes, including GSTM1, GSTT1, and GSTP1, are the most studied in relation to rCC risk (table 4).128 Gst

enzymes are active in the detoxification of polycyclic aro-matic hydrocarbons in tobacco smoke, halogenated sol-vents, and other xenobiotics. Gst genes in general have not been statistically significantly associated with rCC risk, but genotype status has been shown to modify the associations between rCC and tobacco smoke, exposure to tCe or pesticides. Further investigation is needed to clarify these associations.16

NAT2, which encodes N-acetyltransferase 2 and is involved in the metabolism of arylamine in tobacco smoke, has also been studied in relation to rCC. smoking-related risk of developing rCC was found to be higher among individuals carrying the slow acetylator NAT2 geno type,129 consistent with observations in bladder cancer,130 but this result has not yet been replicated.

vitamin D maintains calcium homeostasis and has been shown to have a role in inhibiting cell proliferation and progression in a number of cancers.131 Genes in the vitamin D pathway have been investigated in relation to rCC risk, but findings are inconsistent across the few studies performed.16 the most commonly examined vitamin D pathway gene encodes the vitamin D recep-tor (VDR), which mediates vitamin D activity and regu-lates transcription of other genes involved in cell growth and immunity.132 a study that examined eight vitamin D pathway genes found increased rCC risk associated with variant haplotypes of VDR.133 the same study also exam-ined genes related to lipid peroxidation, blood pressure control, and cellular growth, differentiation, and apop-tosis.134–136 elevated rCC risk was associated with two snPs in the regulatory region of the apolipoprotein e gene, a result that was replicated in a second large study in the us.134 elevated rCC risk was also observed with the apoptosis genes CASP1, CASP5, CASP4 and CASP12, and the blood pressure gene AGT, but replication is needed to confirm these findings (table 5).135,136

High-throughput methods are being used for genome-wide scanning of tagged snPs and copy number altera tions, and large collaborative studies involving a consortium of ongoing case–control and cohort studies of rCC are also underway. these efforts should accel-erate the discovery of common genetic variations and elucidate how their interaction with environmental exposures might influence renal carcinogenesis.

Conclusionsworldwide kidney cancer incidence increased since the early 1970s, until the mid-1990s when it stabilized or declined in many countries. long-term data from Denmark and Connecticut show that an increase in kidney cancer incidence started as early as the 1930s. in the us, the incidence of rCC—the predominant subtype of kidney cancer—rose through the mid-2000s, while rates of rtCC have declined since the 1990s among both black and white populations. long-term worldwide data for kidney cancer subtypes are limited, but recent data from Denmark suggest that renal pelvis cancer incidence began to decline from the late 1980s. the decline in renal pelvis cancer, specifically rtCC, is likely to be due to the decrease in cigarette consumption in industrialized

Table 5 | Genetic variants associated with RCC risk: limited evidence*

Pathway gene

Not known‡ 8q24

Blood pressure control AGT

Cell cycle control CHEK2, CCND1

Cell growth/apoptosis EGFR, TGFB1, CASP1/CASP5/CASP4/CASP12

Cytokine‑related TNF, IL4R

DNA repair XPD, XPA, XRCC4, ERCC6, NBS1

Insulin growth factor IGFBP3

Matrix metalloproteinase MMP1

miRNA processing GEMIN4

One‑carbon (folate) metabolism MTHFR, TYMS

Oxidative stress/inflammation COMT, GPX4, NOS2A

p53 regulation MDM2

T‑cell regulation CTLA4

Vitamin D RXRA

Wnt signaling genes DKK2, DKK3, SFRP4, SMAD7

Xenobiotic metabolism CYP1A1, CYP1B1, GSTP1

*Limited evidence refers to at least one study demonstrating an association. ‡The biological mechanism underlying the 8q24 region’s association with cancer risk has not yet been identified.

rEVIEWS

nrurol_46_MAY10.indd 254 20/4/10 11:18:31



countries, although the removal of phenacetin from most markets around 1980 may also have contributed to the initial decline. most of the increase in detected rCC in the us since the 1980s has occurred for early-stage tumors, a pattern consistent with a downward shift in tumor stage and size, which has been observed in numer-ous clinical series. the rising prevalence of obesity and hypertension—well-established risk factors for rCC—is likely to have contributed to the increase in rCC inci-dence. another established risk factor, cigarette smoking, should have progressively less of a role in rCC develop-ment with decreasing consumption in developed coun-tries, but might become more prominent in developing countries where smoking prevalence shows no sign of declining, and may even be increasing.

accumulating evidence suggests that several other factors—physical activity, alcohol intake, occupational exposure to tCe, and high parity in women—affect rCC risk. the relative contribution of each of these risk factors to rCC incidence in a given population might vary, however, according to the presence of other risk and protective factors, awareness and control of pre-disposing conditions, and surveillance and incidental diagnosis of preclinical tumors. while only a small proportion of rCC occurs within the milieu of familial cancer syndromes, genetic susceptibility and its inter-action with environmental exposure is believed to have

Review criteria

The PubMed database was searched for articles published up to March 1, 2010. The MeSH search terms “kidney neoplasms” and “renal cell carcinoma” were used in combination with the subheadings “epidemiology”, “trends”, and “genetics”, and other MeSH terms “risk factors”, “incidence”, “polymorphism, genetic” and “cohort studies”, and MeSH terms for specific exposures, such as “hypertension”, “obesity”, and “occupations”. Cohort studies and pooled analyses were selected for inclusion in this Review; case–control and other studies were also selected if they provided relevant information.

1. Homer, M. J. et al. (eds). SEER Cancer Statistics Review, 1975–2006, National Cancer Institute. Bethesda, MD [online], http://seer.cancer.gov/csr/1975_2006/ (2009).

2. Sudarshan, S. & Linehan, W. M. Genetic basis of cancer of the kidney. Semin. Oncol. 33, 544–551 (2006).

3. Cheng, L. et al. Molecular and cytogenetic insights into the pathogenesis, classification, differential diagnosis, and prognosis of renal epithelial neoplasms. Hum. Pathol. 40, 10–29 (2009).

4. Curado, M. P. et al. (eds) Cancer Incidence in Five Continents Vol. IX (IARC Scientific Publications No. 160, Lyon, IARC, 2007).

5. Stefanovic, V. & Radovanovic, Z. Balkan endemic nephropathy and associated urothelial cancer. Nat. Clin. Pract. Urol. 5, 105–112 (2008).

6. Cook, M. B. et al. Sex disparities in cancer incidence by period and age. Cancer Epidemiol. Biomarkers Prev. 18, 1174–1182 (2009).

7. Scélo, G. & Brennan, P. The epidemiology of bladder and kidney cancer. Nat. Clin. Pract. Urol. 4, 205–217 (2007).

8. Levi, F. et al. The changing pattern of kidney cancer incidence and mortality in Europe. BJU Int. 101, 949–958 (2008).

9. Devesa, S. S. et al. Comparison of the descriptive epidemiology of urinary tract cancers. Cancer Causes Control 1, 133–141 (1990).

10. Parkin, D. M., Whelan, S. L., Ferlay, J. & Storm, H. Cancer Incidence in Five Continents Vol. I–VIII (IARC CancerBase No. 7, Lyon, 2005).

11. Surveillance Research Program, National Cancer Institute SEER*Stat software. Surveillance, Epidemiology, and End Results (SEER): SEER*Stat Database: Total US, 1969–2006 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics

Branch [online], www.seer.cancer.gov/seerstat (2009).

12. Katz, D. L., Zheng, T., Holford, T. R. & Flannery, J. Time trends in the incidence of renal carcinoma: analysis of Connecticut tumor registry data, 1935–1989. Int. J. Cancer 58, 57–63 (1994).

13. Wihlborg, A. & Johansen, C. Incidences of kidney, pelvis, ureter, and bladder cancer in a nationwide, population‑based cancer registry, Denmark, 1944–2003. Urology doi:10.1016/ j.urology.2009.05.013.

14. Kane, C. J., Mallin, K., Ritchey, J., Cooperberg, M. R. & Carroll, P. R. Renal cell cancer stage migration: analysis of the National Cancer Data Base. Cancer 113, 78–83 (2008).

15. Sánchez‑Martín, F. M., Millán‑Rodríguez, F., Urdaneta‑Pignalosa, G., Rubio‑Briones, J. & Villavicencio‑Mavrich, H. Small renal masses: incidental diagnosis, clinical symptoms, and prognostic factors. Adv. Urol. 2008, 310694 (2008).

16. Chow, W.‑H. & Devesa, S. S. Contemporary epidemiology of renal cell cancer. Cancer J. 14, 288–301 (2008).

17. Surveillance, Epidemiology, and End Results (SEER) SEER*Stat Database: Mortality—All COD: Total US, 1969–2006 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, [online], Underlying mortality data—NCHS, www.cdc.gov/nchs Surveillance Research Program, National Cancer Institute SEER*Stat software, www.seer.cancer.gov/seerstat (2009).

18. McLaughlin, J. K., Lipworth, l., Tarone, R. E. & Blot, W. J. in Cancer Epidemiology and Prevention 3rd edn (eds Schottenfeld, D. & Fraumeni, J. F. Jr) (New York, Oxford University Press, 2006).

19. Zeegers, M. P. A., Tan, F. E. S., Dorant, E. & van den Brandt, P. A. The impact of characteristics of cigarette smoking on urinary tract cancer risk:

a meta‑analysis of epidemiologic studies. Cancer 89, 630–639 (2000).

20. IARC Monographs on the Evaluation of Carcinogenesis risks to Humans. Suppl. 7: Overall evaluations of carcinogenicity: an updating of IARC Monographs Vol. 1–42 International Agency for Research on Cancer, Lyon (1987).

21. IARC Monographs on the Evaluation of Carcinogenesis Risks to Humans: Tobacco smoke and involuntary smoking. International Agency for Research on Cancer, Lyon, 83 (2004).

22. McCredie, M. & Stewart, J. H. Risk factors for kidney cancer in New South Wales—I. Cigarette smoking. Eur. J. Cancer 28A, 2050–2054 (1992).

23. McLaughlin, J. K. et al. Cigarette smoking and cancers of the renal pelvis and ureter. Cancer Res. 52, 254–257 (1992).

24. Hinson, J. A. Reactive metabolites of phenacetin and acetaminophen: a review. Environ. Health Perspect. 49, 71–79 (1983).

25. Henrich, W. L. et al. Analgesics and the kidney: summary and recommendations to the Scientific Advisory Board of the National Kidney Foundation from an ad hoc committee of the National Kidney Foundation. Am. J. Kidney Dis. 27, 162–165 (1996).

26. Friis, S. et al. Cancer risk in persons receiving prescriptions for paracetamol: a Danish cohort study. Int. J. Cancer 97, 96–101 (2002).

27. Mihatsch, M. J., Khanlari, B. & Brunner, F. P. Obituary to analgesic nephropathy—an autopsy study. Nephrol. Dial. Transplant 21, 3139–3145 (2006).

28. Michielsen, P. et al. Non‑phenacetin analgesics and analgesic nephropathy. Nephrol. Dial. Transplant 24, 1253–1259 (2009).

29. Nortier, J. L. et al. Urothelial carcinoma associated with the use of a Chinese herb

an etiologic role in the development of sporadic rCC. notably, however, studies of common genetic variants in rCC risk using candidate-gene approaches have yielded mixed results to date. the rapid advancement in labora-tory technology for genome-wide scanning will allow more-thorough evaluation of common genetic varia-tions. in conjunction with consortium efforts in pooling detailed exposure data and biological samples from well-designed epidemiologic studies, these innovative tech-nologies hold promise for enabling novel discoveries into the genetic determinants of rCC, and elucidating how interaction with environmental factors might influence rCC etiology.


nrurol_46_MAY10.indd 255 20/4/10 11:18:31


http://seer.cancer.gov/csr/1975_2006/

http://seer.cancer.gov/csr/1975_2006/

www.seer.cancer.gov/seerstat

www.cdc.gov/nchs

www.cdc.gov/nchs


(Aristolochia fangchi). N. Engl. J. Med. 342, 1686–1692 (2000).

30. Chen, C.‑J., Chen, C. W., Wu, M.‑M. & Kuo, T.‑L. Cancer potential in liver, lung, bladder and kidney due to ingested inorganic arsenic in drinking water. Br. J. Cancer 66, 888–892 (1992).

31. Hopenhayn‑Rich, C., Biggs, M. L. & Smith, A. H. Lung and kidney cancer mortality associated with arsenic in drinking water in Córdoba, Argentina. Int. J. Epidemiol. 27, 561–569 (1998).

32. Yuan, Y. et al. Kidney cancer mortality: fifty‑year latency patterns related to arsenic exposure. Epidemiology 21, 103–108 (2010).

33. Guo, H.‑R., Chiang, H.‑S., Hu, H., Lipsitz, S. R. & Monson, R. R. Arsenic in drinking water and incidence of urinary cancers. Epidemiology 8, 545–550 (1997).

34. Bunnell, J. E. et al. Possible linkages between lignite aquifers, pathogenic microbes, and renal pelvic cancer in northwestern Louisiana, USA. Environ. Geochem. Health 28, 577–587 (2006).

35. Kurttio, P., Pukkala, E., Kahelin, H., Auvinen, A. & Pekkanen, J. Arsenic concentrations in well water and risk of bladder and kidney cancer in Finland. Environ. Health Perspect. 107, 705–710 (1999).

36. Meliker, J. R., Wahl, R. L., Cameron, L. L. & Nriagu, J. O. Arsenic in drinking water and cerebrovascular disease, diabetes mellitus, and kidney disease in Michigan: a standardized mortality ratio analysis. Environ. Health 6, 4 (2007).

37. Baastrup, R. et al. Arsenic in drinking‑water and risk for cancer in Denmark. Environ. Health Perspect. 116, 231–237 (2008).

38. Han, Y.‑Y., Weissfeld, J. L., Davis, D. L. & Talbott, E. O. Arsenic levels in ground water and cancer incidence in Idaho: an ecologic study. Int. Arch. Occup. Environ. Health 82, 843–849 (2009).

39. Liaw, K.‑L. et al. Possible relation between hypertension and cancers of the renal pelvis and ureter. Int. J. Cancer 70, 265–268 (1997).

40. Chow, W.‑H. et al. Risk of urinary tract cancers following kidney or ureter stones. J. Natl Cancer Inst. 89, 1453–1457 (1997).

41. Chow, W.‑H., Gridley, G., Fraumeni, J. F. Jr & Järvholm, B. Obesity, hypertension, and the risk of kidney cancer in men. N. Engl. J. Med. 343, 1305–1311 (2000).

42. Brock, K. E. et al. Dietary factors and cancers of the renal pelvis and ureter. Cancer Epidemiol. Biomarkers Prev. 15, 1051–1053 (2006).

43. Wilson, R. T. et al. Shared occupational risks for transitional cell cancer of the bladder and renal pelvis among men and women in Sweden. Am. J. Ind. Med. 51, 83–99 (2008).

44. US Department of Health and Human Services. The Health Consequences of Smoking: A report of the Surgeon General (Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. Atlanta, GA, 2004).

45. Hunt, J. D. et al. Renal cell carcinoma in relation to cigarette smoking: meta‑analysis of 24 studies. Int. J. Cancer 114, 101–108 (2005).

46. Thun, M. J., DeLancey, J. O., Center, M. M., Jemal, A. & Ward, E. M. The global burden of cancer: priorities for prevention. Carcinogenesis 31, 100–110 (2010).

47. Forey, B., Hamling, J., Lee, P. & Wald, N. (eds) International Smoking Statistics. A Collection of Historical Data from 30 Economically Developed Countries 2nd edn (London, Oxford University Press, 2002).

48. Sharifi, N. & Farrar, W. L. Perturbations in hypoxia detection: a shared link between hereditary and

sporadic tumor formation? Med. Hypotheses 66, 732–735 (2006).

49. Clague, J. et al. Sensitivity to NNKOAc is associated with renal cancer risk. Carcinogenesis 30, 706–710 (2009).

50. Zhu, Y. et al. BPDE induced lymphocytic chromosome 3p deletions may predict renal cell carcinoma risk. J. Urol. 179, 2416–2421 (2008).

51. Calle, E. E. & Kaaks, R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat. Rev. Cancer 4, 579–591 (2004).

52. Oh, S. W., Yoon, Y. S. & Shin, S. A. Effects of excess weight on cancer incidences depending on cancer sites and histologic findings among men: Korea National Health Insurance Corporation Study. J. Clin. Oncol. 23, 4742–4754 (2005).

53. Pischon, T. et al. Body size and risk of renal cell carcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC). Int. J. Cancer 118, 728–738 (2006).

54. Reeves, G. K. et al. Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study. BMJ 335, 1134–1144 (2007).

55. Adams, K. F. et al. Body size and renal cell cancer incidence in a large US cohort study. Am. J. Epidemiol. 168, 268–277 (2008).

56. Renehan, A. G. et al. Body‑mass index and incidence of cancer: a systematic review and meta‑analysis of prospective observational studies. Lancet 371, 569–578 (2008).

57. World Cancer Research Fund, American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective (AICR, Washington DC, 2007).

58. Nguyen, D. M. & El‑Serag, H. B. The epidemiology of obesity. Gastroenterol. Clin. N. Am. 39, 1–7 (2010).

59. Popkin, B. M. The nutrition transition: an overview of world patterns of change. Nutr. Rev. 62, S140–S143 (2004).

60. Flegal, K. M., Carroll, M. D., Ogden, C. L. & Curtin, L. R. Prevalence and trends in obesity among US adults, 1999–2008. JAMA 303, 235–241 (2010).

61. Klinghoffer, Z., Yang, B., Kapoor, A. & Pinthus, J. H. Obesity and renal cell carcinoma: epidemiology, underlying mechanisms and management considerations. Expert Rev. Anticancer Ther. 9, 975–987 (2009).

62. Kearney, P. M. et al. Global burden of hypertension: analysis of worldwide data. Lancet 365, 217–223 (2005).

63. Mittal, B. V. & Singh, A. K. Hypertension in the developing world: challenges and opportunities. Am. J. Kidney Dis. 55, 590–598 (2010).

64. Steffens, J. et al. Renin‑producing renal cell carcinomas—clinical and experimental investigations on a special form of renal hypertension. Urol. Res. 20, 111–115 (1992).

65. Maitland, M. L. et al. Ambulatory monitoring detects sorafenib‑induced blood pressure elevations on the first day of treatment. Clin. Cancer Res. 15, 6250–6257 (2009).

66. Choi, M. Y. et al. The effect of hypertension on the risk for kidney cancer in Korean men. Kidney Int. 67, 647–652 (2005).

67. Vatten, L. J. et al. Blood pressure and renal cancer risk: the HUNT Study in Norway. Br. J. Cancer 97, 112–114 (2007).

68. Weikert, S. et al. Blood pressure and risk of renal cell carcinoma in the European Prospective Investigation into Cancer and Nutrition. Am. J. Epidemiol. 167, 438–446 (2008).

69. Nicodemus, K. K., Sweeney, C. & Folsom, A. R. Evaluation of dietary, medical and lifestyle risk factors for incident kidney cancer in postmenopausal women. Int. J. Cancer 108, 115–121 (2004).

70. Flaherty, K. T. et al. A prospective study of body mass index, hypertension, and smoking and the risk of renal cell carcinoma (United States). Cancer Causes Control 16, 1099–1106 (2005).

71. Setiawan, V. W. et al. Risk factors for renal cell cancer: the multiethnic cohort. Am. J. Epidemiol. 166, 932–940 (2007).

72. Schouten, L. J. et al. Hypertension, antihypertensives and mutations in the von Hippel–Lindau gene in renal cell carcinoma: results from the Netherlands Cohort Study. J. Hypertens. 23, 1997–2004 (2005).

73. Gago‑Dominguez, M. et al. Lipid peroxidation: a novel and unifying concept of the etiology of renal cell carcinoma (United States). Cancer Causes Control 13, 287–293 (2002).

74. Inoue, M. et al. Diabetes mellitus and the risk of cancer: results from a large‑scale population‑based cohort study in Japan. Arch. Intern. Med. 166, 1871–1877 (2009).

75. Vajdic, C. M. et al. Cancer incidence before and after kidney transplantation. JAMA 296, 2823–2831 (2006).

76. Stewart, J. H. et al. The pattern of excess cancer in dialysis and transplantation. Nephrol. Dial. Transplant. 24, 3225–3231 (2009).

77. Klatte, T. et al. Features and outcomes of renal cell carcinoma of native kidneys in renal transplant recipients. BJU Int. doi:10.1111/ j.1464–410X.2009.08941.x.

78. Bonsib, S. M. Renal cystic diseases and renal neoplasms: a mini‑review. Clin. J. Am. Soc. Nephrol. 4, 1998–2007 (2009).

79. Bassal, M. et al. Risk of selected subsequent carcinomas in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J. Clin. Oncol. 24, 476–483 (2006).

80. Wiklund, F. et al. Risk of bilateral renal cell cancer. J. Clin. Oncol. 27, 3737–3741 (2009).

81. Lambe, M. et al. Pregnancy and risk of renal cell cancer: a population‑based study in Sweden. Br. J. Cancer 86, 1425–1429 (2002).

82. Kabat, G. C. et al. A cohort study of reproductive and hormonal factors and renal cell cancer risk in women. Br. J. Cancer 96, 845–849 (2007).

83. Molokwu, J. C., Prizment, A. E. & Folsom, A. R. Reproductive characteristics and risk of kidney cancer: Iowa Women’s Health Study. Maturitas 58, 156–163 (2007).

84. Lee, J. E., Hankinson, S. E. & Cho, E. Reproductive factors and risk of renal cell cancer: The Nurses’ Health Study. Am. J. Epidemiol. 169, 1243–1250 (2009).

85. Setiawan, V. W., Kolonel, L. N. & Henderson, B. E. Menstrual and reproductive factors and risk of renal cell cancer in the Multiethnic Cohort. Cancer Epidemiol. Biomarkers Prev. 18, 337–340 (2009).

86. McTiernan, A. Mechanisms linking physical activity with cancer. Nat. Rev. Cancer 8, 205–211 (2008).

87. van Dijk, B. A. et al. Relation of height, body mass, energy intake, and physical activity to risk of renal cell carcinoma: results from the Netherlands Cohort Study. Am. J. Epidemiol. 160, 1159–1167 (2004).

88. Mahabir, S. et al. Physical activity and renal cell cancer risk in a cohort of male smokers. Int. J. Cancer 108, 600–605 (2004).

89. Moore, S. C. et al. Physical activity during adulthood and adolescence in relation to renal cell cancer. Am. J. Epidemiol. 168, 149–157 (2008).

rEVIEWS

nrurol_46_MAY10.indd 256 20/4/10 11:18:31



90. Richardson, C. R. et al. A meta‑analysis of pedometer‑based walking interventions and weight loss. Ann. Fam. Med. 6, 69–77 (2008).

91. Pialoux, V., Brown, A. D., Leigh, R., Friedenreich, C. M. & Poulin, M. J. Effect of cardiorespiratory fitness on vascular regulation and oxidative stress in postmenopausal women. Hypertension 54, 1014–1020 (2009).

92. Solomon, T. P. J. et al. Randomized trial on the effects of a 7‑d low‑glycemic diet and exercise intervention on insulin resistance in older obese humans. Am. J. Clin. Nutr. 90, 1222–1229 (2009).

93. Lee, J. E. et al. Intakes of fruit, vegetables, and carotenoids and renal cell cancer risk: a pooled analysis of 13 prospective studies. Cancer Epidemiol. Biomarkers Prev. 18, 1730–1739 (2009).

94. Lee, J. E. et al. Intakes of fruits, vegetables, vitamins A, C, and E, and carotenoids and risk of renal cell cancer. Cancer Epidemiol. Biomarkers Prev. 15, 2445–2452 (2006).

95. Weikert, S. et al. Fruits and vegetables and renal cell carcinoma: findings from the European Prospective Investigation into Cancer and Nutrition (EPIC). Int. J. Cancer 118, 8133–8139 (2006).

96. van Dijk, B. A. et al. Carotenoid and vitamin intake, von Hippel–Lindau gene mutations and sporadic renal cell carcinoma. Cancer Causes Control 19, 125–134 (2008).

97. Bertoia, M. et al. No association between fruit, vegetables, antioxidant nutrients and risk of renal cell carcinoma. Int. J. Cancer 126, 1504–1512 (2010).

98. Lee, J. E. et al. Fat, protein, and meat consumption and renal cell cancer risk: a pooled analysis of 13 prospective studies. J. Natl Cancer Inst. 100, 1695–1706 (2008).

99. Allen, N. E. et al. A prospective analysis of the association between macronutrient intake and renal cell carcinoma in the European Prospective Investigation into Cancer and Nutrition. Int. J. Cancer 125, 982–987 (2009).

100. Alexander, D. D. & Cushing, C. A. Quantitative assessment of red meat or processed meat consumption and kidney cancer. Cancer Detect. Prev. 32, 340–351 (2009).

101. Prentice, R. L. et al. Biomarker‑calibrated energy and protein consumption and increased cancer risk among postmenopausal women. Am. J. Epidemiol. 169, 977–989 (2009).

102. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Some industrial chemicals. International Agency for Research on Cancer, Lyon, 60 (1994).

103. Törnqvist, M. Acrylamide in food: the discovery and its implications: a historical perspective. Adv. Exp. Med. Biol. 561, 1–19 (2005).

104. Mucci, L. A. & Adami, H. O. The plight of the potato: Is dietary acrylamide a risk factor for human cancer? J. Natl Cancer Inst. 101, 618–621 (2009).

105. Mucci, L. A., Dickman, P. W., Steineck, G., Adami, H.‑O. & Augustsson, K. Dietary acrylamide and cancer of the large bowel, kidney, and bladder: absence of an association in a

population‑based study in Sweden. Br. J. Cancer 88, 84–89 (2003).

106. Mucci, L. A., Lindblad, P., Steineck, G. & Adami, H.‑O. Dietary acrylamide and risk of renal cell cancer. Int. J. Cancer 109, 774–776 (2004).

107. Hogervorst, J. G., Schouten, L. J., Konings, E. J., Goldbohm, R. A. & van den Brandt, P. A. Dietary acrylamide intake and the risk of renal cell, bladder, and prostate cancer. Am. J. Clin. Nutr. 87, 1428–1438 (2008).

108. Lee, J. E. et al. Alcohol intake and renal cell cancer in a pooled analysis of 12 prospective studies. J. Natl Cancer Inst. 99, 801–810 (2007).

109. Lee, J. E. et al. Intakes of coffee, tea, milk, soda and juice and renal cell cancer in a pooled analysis of 13 prospective studies. Int. J. Cancer 121, 2246–2253 (2007).

110. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Dry cleaning, some chlorinated solvents and other industrial chemicals. International Agency for Research on Cancer, Lyon, 63 (1995).

111. Chiu, W. A., Caldwell, J. C., Keshava, N. & Scott, C. S. Key scientific issues in the health risk assessment of trichloroethylene. Environ. Health Perspect. 114, 1445–1449 (2006).

112. Scott, C. S. & Chiu, W. A. Trichloroethylene cancer epidemiology: a consideration of select issues. Environ. Health Perspect. 114, 1471–1478 (2006).

113. Kelsh, M. A., Alexander, D. D., Mink, P. J. & Mandel, J. H. Occupational trichloroethylene exposure and kidney cancer: a meta‑analysis. Epidemiology 21, 95–102 (2010).

114. Caldwell, J. C., Keshava, N. & Evans, M. V. Difficulty of mode of action determination for trichloroethylene: an example of complex interactions of metabolites and other chemical exposures. Environ. Mol. Mutag. 49, 142–154 (2008).

115. Hu, H. et al. The relationship of bone and blood lead to hypertension. The Normative Aging Study. JAMA 275, 1171–1176 (1996).

116. Tellez‑Plaza, M., Navas‑Acien, A., Crainiceanu, C. M. & Guallar, E. Cadmium exposure and hypertension in the 1999–2004 National Health and Nutrition Examination Survey (NHANES). Environ. Health Perspect. 116, 51–56 (2008).

117. Huang, M. et al. Risk assessment of low‑level cadmium and arsenic on the kidney. J. Toxicol. Environ. Health 72, 1493–1498 (2009).

118. Navas‑Acien, A. et al. Blood cadmium and lead and chronic kidney disease in US adults: a joint analysis. Am. J. Epidemiol. 170, 1156–1164 (2009).

119. Kaelin, W. G. Jr. von Hippel–Lindau disease. Annu. Rev. Pathol. Mech. Dis. 2, 145–173 (2007).

120. Clague, J. et al. Family history and risk of renal cell carcinoma: results from a case‑control study and systematic meta‑analysis. Cancer Epidemiol. Biomarkers Prev. 18, 801–807 (2009).

121. Shiao, Y.‑H. Genetic signature for human risk assessment: lessons from trichloroethylene. Environ. Mol. Mutag. 50, 68–77 (2009).

122. Brauch, H. et al. Trichloroethylene exposure and sporadic somatic mutations in patients with renal cell carcinoma. J. Natl Cancer Inst. 91, 854–861 (1999).

123. Charbotel, B. et al. Trichloroethylene exposure and somatic mutations of the VHL gene in patients with renal cell carcinoma. J. Occup. Med. Toxicol. 2, 13–19 (2007).

124. Nickerson, M. L. et al. Improved identification of von Hippel–Lindau gene alterations in clear cell renal tumors. Clin. Cancer Res. 14, 4726–4734 (2008).

125. Chen, M. et al. Genome‑wide profiling of chromosomal alterations in renal cell carcinoma using high‑density single nucleotide polymorphism arrays. Int. J. Cancer 125, 2342–2348 (2009).

126. Wu, X. et al. Telomere dysfunction: a potential cancer predisposition factor. J. Natl Cancer Inst. 95, 1211–1218 (2003).

127. Xing, J. et al. Mitochondrial DNA content: its genetic heritability and association with renal cell carcinoma. J. Natl Cancer Inst. 100, 1104–1112 (2008).

128. Simic, T., Savic‑Radojevic, A., Pljesa‑Ercegovac, M., Matic, M. & Mimic‑Oka, J. Glutathione S‑transferases in kidney and urinary bladder tumors. Nat. Rev. Urol. 6, 281–289 (2009).

129. Semenza, J. C. et al. Gene–environment interactions in renal cell carcinoma. Am. J. Epidemiol. 153, 851–859 (2001).

130. García‑Closas, M. et al. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta‑analyses. Lancet 366, 649–659 (2005).

131. Bouillon, R. et al. Vitamin D and cancer. J. Steroid Biochem. Mol. Biol. 102, 156–162 (2006).

132. Valdivielso, J. M. & Fernandez, E. Vitamin D receptor polymorphisms and diseases. Clin. Chim. Acta 371, 1–12 (2006).

133. Karami, S. et al. Analysis of SNPs and haplotypes in vitamin D pathway genes and renal cancer risk. PLoS ONE 4, e7013 (2009).

134. Moore, L. E. et al. Apolipoprotein E/C1 locus variants modify renal cell carcinoma risk. Cancer Res. 69, 8001–8008 (2009).

135. Andreotti, G. et al. Variants in blood pressure genes and the risk of renal cell carcinoma. Carcinogenesis doi:10.1093/carcin/bgp321.

136. Dong, L. M. et al. An analysis of growth, differentiation and apoptosis genes with risk of renal cancer. PLoS ONE 4, e4895 (2009).

AcknowledgmentsThe authors express their appreciation to the cancer registries contributing data to the IARC Cancer Incidence in Five Continents and the NCI Surveillance, Epidemiology, and End Results (SEER) Program, and to the dedicated program staff of the IARC and NCI. They also thank David Check of the Division of Cancer Epidemiology and Genetics, NCI for figure preparation using tabulated data generated from NCI’s SEER and IARC’s Cancer Incidence in Five Continents series. This Review was supported by the Intramural Research Program of the National Institutes of Health.


nrurol_46_MAY10.indd 257 20/4/10 11:18:31


epidemiology and risk factors for kidney cancer

Documents