Kidney Cancer Causes

Kidney cancer accounts for 2.4% of all cancers in the world, with more than 330,000 new cases diagnosed each year, and globally, kidney cancer (also called renal cancer) is the seventh most common cancer overall.¹ 

Kidney cancer develops in the renal parenchyma, the functional part of the kidney, making up more than 9 out of 10 renal cancers in adults.¹ Additionally, clear cell renal cell carcinomas account for about 70% of all kidney cancer cases.¹ 

Other types include transitional cell carcinomas of the renal pelvis and renal sarcoma, which is a rare tumour of the kidney.^1,2 

One of the most distinctive epidemiological characteristics of kidney cancer is its wide geographic and temporal variation in incidence rates. There are only a few documented risk factors, including tobacco smoking, obesity, and hypertension.¹ 

In this article, we’ll discuss the risk factors and genetic factors that may contribute to kidney cancer. 

Risk factors

A wide range of factors have been found to increase the risk of kidney cancer. These factors include lifestyle-related factors, genetic factors, medical and environmental factors, as well as age and gender.¹ 

We will discuss each in greater detail in the following paragraphs.

Lifestyle-related factors

The lifestyle-related factors can be divided into two categories – established and unsuspected. A detailed description can be found in Table 1. 

Table 1. Lifestyle-related risk factors associated with kidney cancer

Cigarette smoking

Smoking is still a causal risk factor for renal cell cancer. According to the International Agency for Research on Cancer (IARC) and the U.S. Surgeon General and risk increased about 50% in assigned male at birth (AMAB) and 20% in assigned female at birth (AFAB) smokers.¹

It is still hypothesised that smoking increases the risk of renal cell cancer through chronic tissue hypoxia caused by carbon monoxide exposure and smoking-related conditions such as chronic obstructive pulmonary disease.³ 

Moreover, patients with kidney cancer displayed a higher level of DNA damage in their peripheral blood lymphocytes induced by tobacco-specific N-nitrosamines compared with controls.⁴ 

Obesity 

It is estimated that excess body weight is responsible for over 40% of renal cell cancers in the United States and over 30% in Europe.⁵

According to different studies conducted worldwide, it was found that overweight and obese individuals elevated subsequent risks of renal cell cancer in a dose-response manner, which were estimated to be 24% for men and 34% for women for each five kilogram increase in body mass index (BMI).^1,7 Finally, a number of mechanisms have been hypothesised as being responsible for the development of renal cell cancer in obese individuals, but no direct evidence has been found in humans. 

These 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.⁸

Hypertension

Most studies strongly suggest that hypertension contributes to the development of renal cell cancer and report an association with a history of long-term hypertension. In addition, Researchers generally found increased kidney cancer risks with rising blood pressure levels in studies with baseline blood pressure measurements.¹ 

Similarly, a Swedish study with sequential blood pressure measurements showed that renal cell cancer risk increases with further elevation of blood pressure and decreases with reduction in blood pressure over time.¹ 

Nevertheless, the biological mechanisms responsible for the association between hypertension and renal cell cancer are unclear, but it is hypothesised that chronic renal hypoxia and formation of reactive oxygen species may play a role.^3,9 

Physical activity 

Despite limited data, most studies suggest that physical activity reduces the risk of renal cell cancer. It has even been demonstrated in some cohort studies that there is a dose-response relationship, with higher levels of activity leading to a greater reduction in risk. 

As a result of physical activity, body weight and blood pressure can be reduced, insulin sensitivity can be improved, and chronic inflammation and oxidative stress can be reduced – all of which may help lower the risk of cancer.¹

Occupation

Generally, renal cell cancer is not classified as an occupational disease, but certain occupations and industrial exposures, especially to trichloroethylene (TCE), have been linked to an increased risk. 

It has been found that TCE, a commonly used metal degreaser, has a consistent link to renal cell cancer across multiple research designs and populations, suggesting a possible true association. 

The pharmacokinetics and co-exposures of TCE, as well as the study's limitations, prevent a definitive causal conclusion. 

Finally, the evidence for an increased risk of renal cell cancer has not been consistent for other industrial agents such as cadmium and uranium, nor for environmental exposures such as arsenic, nitrate, and radon in drinking water.¹

Genetic factors

Current studies suggest that inherited renal cell cancer occurs in several cancer syndromes, most notably the von Hippel-Lindau (VHL) syndrome.¹ 

Other examples of inherited renal cell cancer include hereditary leiomyomatosis and aggressive papillary carcinoma syndrome, hereditary papillary carcinoma, Birt-Hogg-Dubé syndrome, and tuberous sclerosis syndrome.² 

In VHL syndrome, the VHL gene is altered, and family members are predisposed to a variety of diseases, including renal cell carcinoma of the clear cell subtype.¹⁰ 

Despite familial syndromes accounting for a small percentage of renal cell cancer (RCC) cases, having a first-degree relative with RCC doubles the risk. In addition, sporadic RCC development may be influenced by exposure to the environment and genetic susceptibility.¹¹ 

Gender

Many cohort studies have linked pregnancy to an increased risk of renal cell cancer in women, but not all of them have supported this conclusion. 

An AFAB individual who has given birth faces an increased risk of 40% to 90% compared to a nulliparous AFAB person, and this risk increases with the number of childbirths.¹ 

There has also been an inverse association with age at first birth, with the highest level of risk among AFAB people who gave birth to multiple children during a relatively young pregnancy.¹² 

The incidence of kidney cancer in AMAB individuals is approximately twice that of AFAB people, according to epidemiological studies. 

There is a 2:1 AMAB-to-AFAB incidence ratio that has remained constant across different ages, years, and regions. In addition, this information is supported by data from the Surveillance, Epidemiology, and End Results (SEER) database (2001–2016) in the US, along with global and regional cancer registries.¹³ 

Finally, from 1990 to 2013, kidney cancer incidence grew by 23.04% globally, disproportionately among males (31.19%) compared with females (8.79%).¹⁴ 

FAQs

How common is kidney cancer worldwide?

Every year, more than 330,000 new cases of kidney cancer are diagnosed worldwide. It makes up about 2.4% of all cancers globally and is the seventh most common cancer in the world.

What is the most common type of kidney cancer?

Over 90% of all adult kidney cancers and about 70% of all kidney cancer cases are caused by renal cell carcinoma (RCC).

How does gender influence kidney cancer risk?

In comparison to AFAB individuals, AMAB individuals are approximately twice as likely to develop kidney cancer. There is a 2:1 ratio across all ages and regions. The global incidence of the disease increased more in AMAB people (31.19%) than in AFAB people (8.79%) from 1990 to 2013.

Summary 

There are more than 330,000 kidney cancer cases worldwide each year, making kidney cancer the seventh most common cancer in the world. It primarily arises from the renal parenchyma, with risk influenced by various factors. 

A number of lifestyle-related risks include the use of tobacco, which increases risk by 50% in men and 20% in women; obesity, which exceeds 40% in the United States; and hypertension, particularly with long-term elevated blood pressure. 

Exercise appears to reduce risk by reducing weight, blood pressure, insulin sensitivity, and inflammation. While causality has yet to be established, occupational exposure to trichloroethylene (TCE) has consistently been linked with increased risk. People with a first-degree relative with renal cell cancer have a double risk of developing the disease, especially in rare hereditary syndromes like von Hippel-Lindau. 

Incidence is also influenced by gender, and the risk to AMAB people is twice that of AFAB individuals – a pattern that has remained consistent despite the passage of time and geography. Additionally, parous individuals face a higher risk of pregnancy complications, especially at younger ages and after more pregnancies.