Diabetes mellitus and incidence and mortality of kidney cancer: A meta-analysis

doi:10.1016/j.jdiacomp.2013.01.004

Journal of Diabetes and its Complications

Volume 27, Issue 4, July–August 2013, Pages 357-364

https://doi.org/10.1016/j.jdiacomp.2013.01.004 Get rights and content

Abstract

Background

Diabetes is associated with increased risk of a spectrum of cancers, but there are few meta-analyses on the association between diabetes and kidney cancer. We performed a meta-analysis of case–control studies and cohort studies to address the incidence and mortality of kidney cancer in diabetes.

Methods

Studies were identified by searching PubMed database and manual assessment of the cited references in the retrieved articles. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were estimated using a random-effect model. Study quality was assessed using the Newcastle–Ottawa scale.

Results

A total of 24 studies were included. We found that diabetes was significantly associated with increased risk of kidney cancer (RR = 1.40, 95% CI = 1.16 to 1.69), and the results were consistent between case–control and cohort studies. A slightly stronger positive relation was observed in women (RR = 1.47, 95% CI = 1.18 to 1.83) than in men (RR = 1.28, 95% CI = 1.10 to 1.48). Additional analyses indicated that the increased risk of kidney cancer was independent of alcohol consumption, body mass index (BMI)/obesity and smoking. However, there was no association between diabetes and mortality of kidney cancer (RR = 1.12, 95% CI = 0.99 to 1.20), without heterogeneity (P = 0.419, I² = 1.8%).

Conclusions

Diabetes mellitus may increase the risk of kidney cancer in both women and men.

Introduction

Cancer is one of major causes of death in the world and an estimated 12.7 million new cancer cases and 7.6 million cancer deaths occurred annually, in which approximately 271,000 new cases of kidney cancer were diagnosed (Jemal et al., 2011). However, the aetiology of kidney cancer remains largely elusive, although increased risk of the disease has been reported in subjects who have an older age, and are cigarette smokers, overweight and obese (Ljungberg et al., 2011). A number of studies have found that diabetes mellitus (DM) confers a higher risk of cancer, notably of breast cancer (Larsson, Mantzoros, & Wolk, 2007), colorectal cancer (Jiang et al., 2011), pancreatic cancer (Ben et al., 2011) and endometrial cancer (Friberg, Orsini, Mantzoros, & Wolk, 2007). Several hypotheses on biological mechanisms have been proposed to explain the plausible causal association between DM and risk of cancer. In additional to the increased risk of incident cancer, DM may also increase the risk of all-cause mortality among people with cancer (Barone et al., 2008). It is suggested that abnormal metabolism, including hyperglycemia (Yang & Chan, 2012) and hyperinsulinemia (Rosta, 2011), may promote cancer development. Although a large number of epidemiological studies have investigated the association between diabetes and kidney cancer, there are few meta-analyses addressing the association between DM and kidney cancer, especially mortality from kidney cancer. The only meta-analysis of 9 cohort studies between diabetes and risk of kidney cancer did not include case–control studies, did not consider the association between DM and kidney cancer mortality and did not control for the factors such as geographic area, diabetes ascertainment, study quality and alcohol consumption (Larsson & Wolk, 2011).

This meta-analysis aimed to quantitatively summarize results from published cohort and case–control studies to provide a more precise estimate of the association between diabetes and incidence and mortality of kidney cancer with study design, diabetes ascertainment, study quality and potential confounders being taken into consideration.

Section snippets

Retrieval of studies

We conducted a literature search of PubMed database (January 1960 through February 2012, human, published in the English language) for cohort and case–control studies evaluating the effect of diabetes on the risk of kidney cancer with the following medical subject heading terms and / or text words: ‘diabetes or diabetes mellitus’, combined with ‘kidney cancer’, ‘renal cell cancer or renal cell carcinoma’. In addition, we reviewed the reference lists of retrieved articles and recent reviews. Two

Characteristics of the subjects in selected studies

Detailed search procedures are summarized in Fig. 1. All the full text of the 29 identified articles was retrieved for detailed evaluation. Of them, 5 articles were further excluded due to not meeting the inclusion criteria, including 2 studies with univariate analyses only (Goodman et al., 1986, Wang et al., 2012), 1 study being on type 1 diabetes only (Zendehdel et al., 2003), and 2 studies (Lindblad et al., 1999, Washio et al., 2007) being already included in other two retrieved articles (

Discussion

Our meta-analysis suggests that DM may increase risk of kidney cancer by about 40%. The summary estimates of RR were consistent in cohort studies and case control studies, and in North America and in Asia, although we failed to detect a significant association in studies conducted in Europe. The positive association was stronger for total or unspecified kidney cancer than for renal cell carcinoma, indicating that diabetes may have different effects on parenchyma and renal pelvis. The positive

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We investigated the association between hepatic and metabolic factors and renal cancer risk.
This population-based cohort study included cancer-free individuals who underwent general health evaluation (January to December 2010) at the Korean National Health Insurance Service and followed-up through 2017. Hazard ratios (HR) and 95% confidence intervals (CI), determined by adjusted Cox regression analysis were used to investigate the effect of variables on renal cancer risk.
Among 4,518,704 subjects, 6531 patients developed renal cancer. Adjusted analyses of epidemiological factors and BMI (body mass index) (Model I) showed serum high-density lipoprotein cholesterol (HDL-C) ≥60 mg/dL (adjusted HR [aHR] 0.88, 95% CI, 0.81–0.95) reduced renal cancer risk comparing to low HDL-C, whereas hepatitis B virus (HBV) antigen (aHR 1.41, 95% CI 1.19–1.68) and chronic HBV infection (aHR 1.65, 95% CI 1.26–2.17) increased its risk. Higher BMI increased renal cancer risk in dose-dependent manner (P for trend <0.001). This association persisted after adjustment for epidemiological factors and waist circumference (Model II). Sex-specific analyses showed similar effect of HBV antigen and chronic HBV infection in both sexes. Normal (50-59 mg/dL in women) or high (≥60 mg/dL in men) HDL-C reduced renal cancer risk. Alcohol consumption increased kidney cancer risk in age ≥ 60 years, but it had no association with renal cancer in age < 60 years.
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Previous studies have reported on incidence and mortality patterns for individual genitourinary cancers in the USA. However, these studies addressed individual cancer types rather than genitourinary cancers overall.
To comprehensively examine disparities and trends in the incidence and mortality for the four major genitourinary cancers (bladder, kidney, prostate, and testis) in the USA.
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Age-adjusted incidence and death rates were calculated using SEER*Stat software. Temporal trends were analyzed using Joinpoint regression for a two-sided significance level of p < 0.05.
Incidence and mortality rates for bladder and kidney cancers were two to four times higher for men than for women. Among non-Hispanic White individuals, the highest incidence rates were found in the Northeast for bladder cancer and in Appalachia for kidney cancer, whereas the highest death rates for prostate cancer were found in the West. Incidence rates increased for cancers of the kidney and testis and for advanced-stage prostate cancer in almost all racial/ethnic populations and for bladder cancer in the American Indian/Alaska Native population. Death rates increased for testicular cancer in the Hispanic population and stabilized for prostate cancer among White and Asian American/Pacific Islander men after a steady decline since the early 1990s. Study limitations include misclassification of race/ethnicity on medical records and death certificates.
We found persistent sociodemographic disparities and unfavorable trends in incidence or mortality for all four major genitourinary cancers. Future studies should elucidate the reasons for these patterns.
In the USA, rates of cancer cases are increasing for kidney, testis, and advanced-stage prostate cancers in the overall population, and for bladder cancer in the American Indian/Alaska Native population. Differences in the rates by sex and race/ethnicity remain.
The biological and pharmacological connections between diabetes and various types of cancer
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Their results revealed that the standardized incidence ratio (SIR) for kidney cancer in individuals suffering from diabetes mellitus compared to the general ones was 1.4 (95% confidence interval (CI): 1.2–1.6) for males and 1.7 (95% CI: 1.4–1.9) for females [66]. Through a meta-analysis, including a total of 18 studies, it has been shown that kidney cancer has a positive link with diabetes (relative risk (RR): 1.40; 95% CI: 1.16–1.69) [67]. A research performed in China, for instance, found that diabetes individuals had a substantially increased risk for kidney cancer (SIR: 1.6 (1.3–2.0) in men and 1.7 (1.3–2.3) in women) [68].
Diabetes and cancer incidence have risen tremendously over the years. Additionally, both cancer and diabetes share numerous risks, such as overweight, inactive lifestyles, older age, and smoking. Numerous methods have been suggested to connect obesity and diabetes to cancer advancements, such as increasing insulin/ Insulin-like growth factor I (IGF-1) signaling, lipid and glucose uptake and metabolism, shifts in the cytokine, chemokine, and adipokine profile also variations in the adipose tissue immediately adjacent to cancer spots. Diabetes has been found to have a complicated cancer-causing mechanism involving excessive reactive oxygen species (ROS) production, loss of critical macromolecules, chronic inflammation, and delayed repair, all of which contribute to carcinogenesis. Diabetes-associated epithelial-to-mesenchymal transition and endothelial-to-mesenchymal transition lead to the formation of cancer-associated fibroblasts in tumors by enabling tumor cells to extravasate via the endothelium and epithelium. This study aims to describe the correlation between diabetes and cancer, as well as summarize the molecular connections and shared pathways such as sex hormones, hyperglycemia, inflammation, insulin axis, metabolic symbiosis, and endoplasmic reticulum (ER) stress that exist between them.
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This suggests that these risk factors are not strongly predictive of kidney cancer or that they are strongly associated with other included risk factors. This conflicts with the existing literature, which suggests that hypertension and diabetes have an independent positive association with kidney cancer, although in the case of diabetes this has not been well characterised [12,35,37,38]. None of the biomarker risk factors were included in more than one study (although some are used in two models developed in the same study [25]).
Early detection of kidney cancer improves survival; however, low prevalence means that population-wide screening may be inefficient. Stratification of the population into risk categories could allow for the introduction of a screening programme tailored to individuals.
This review will identify and compare published models that predict the risk of developing kidney cancer in the general population.
A search identified primary research reporting or validating models predicting the risk of kidney cancer in Medline and EMBASE. After screening identified studies for inclusion, we extracted data onto a standardised form. The risk models were classified using the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines and evaluated using the PROBAST assessment tool.
The search identified 15 281 articles. Sixty-two satisfied the inclusion criteria; performance measures were provided for 11 models. Some models predicted the risk of prevalent undiagnosed disease and others future incident disease. Six of the models had been validated, two using external populations. The most commonly included risk factors were age, smoking status, and body mass index. Most of the models had acceptable-to-good discrimination (area under the receiver-operating curve >0.7) in development and validation. Many models also had high specificity; however, several had low sensitivity. The highest performance was seen for the models using only biomarkers to detect kidney cancer; however, these were developed and validated in small case-control studies.
We identified a small number of risk models that could be used to stratify the population according to the risk of kidney cancer. Most exhibit reasonable discrimination, but a few have been validated externally in population-based studies.
In this review, we looked at mathematical models predicting the likelihood of an individual developing kidney cancer. We found several suitable models, using a range of risk factors (such as age and smoking) to predict the risk for individuals. Most of the models identified require further testing in the general population to confirm their usefulness.
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The latest meta-analysis by Bao et al. (2013), which summarized findings from 11 cohort and 7 case-control studies, also reported a positive association between diabetes and an increased risk of kidney cancer that remained after adjustment for BMI. Similar to the meta-analysis by Larsson et al. (2011), the association was stronger in females [RR (95% CI) = 1.47 (1.18, 1.83)] versus males [RR (95% CI) = 1.28 (1.10, 1.48)] [14]. In parallel to our study, the Vitamin and Lifestyle study found a significant association in unadjusted but not in multivariable-adjusted model [HR (95% CI) = 1.39 (0.92, 2.09)] [28], while the population-based case-control study in Taiwan found no association in either unadjusted or multivariable-adjusted model [29].
Many studies have reported a positive association between diabetes and kidney cancer. However, it is unclear whether diabetes is a risk factor for kidney cancer independent of other risk factors, such as obesity and hypertension. We comprehensively examined the association of diabetes and its duration with incident kidney cancer in the prospective cohort Iowa Women’s Health Study (1986–2011).
Diabetes status was self-reported at baseline (1986) and on five follow-up questionnaires. Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of baseline and time-dependent diabetes with the risk of incident kidney cancer.
During the 25 years of follow-up, 245 cases of kidney cancer occurred among 36,975 post-menopausal women. In an age-adjusted model, there was a significant association between time-dependent diabetes and the risk of kidney cancer [HR (95% CI) = 1.76 (1.26, 1.45)]; the association was attenuated after multivariable adjustment for age, body mass index (BMI), waist-to-hip ratio (WHR), hypertension, physical activity, diuretic use, pack-years of smoking, alcohol intake, and total caloric intake [HR = 1.35 (0.94, 1.94)]. However, among non-obese women or women with a waist circumference less than 34.6 in., diabetes was significantly associated with kidney cancer risk: for time-dependent diabetes, HRs (95% CIs) were 1.82 (1.10, 3.00) among those with BMI < 30 kg/m² and 2.18 (1.08, 4.38) among those with a waist circumference <34.6 in..
Our results suggest that diabetes is associated with kidney cancer risk among non-obese post-menopausal women.
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The incidence of type 2 diabetes mellitus (T2DM) has sharply increased worldwide over the past few decades, with an estimated 642 million affected people expected by 2040 [6]. Recently, several studies have shown that T2DM can increase the risk of several cancers, including urological neoplasm's such as BC (Relative risk [RR] = 1.30, 95% confidence interval [CI] = 1.18–1.43) [7,8] and kidney cancer (RR = 1.40, 95% CI = 1.16–1.69) [9]. On the other hand, there is a controversy regarding the prognostic role of T2DM in diabetic people diagnosed with cancer, with a potential negative influence of T2DM reported in some tumors—e.g., breast cancer [10], and conflicting results obtained in others [11,12].
The aim of this multicenter study was to investigate the prognostic role of type 2 diabetes mellitus (T2DM) comorbidity in a large multi-institutional cohort of patients with primary T1HG/G3 non–muscle-invasive bladder cancer (NMIBC) treated with transurethral resection of the bladder (TURB).
A total of 1,172 patients with primary T1 HG/G3 who had NMIBC on re-TURB and who received adjuvant intravesical bacillus Calmette-Guérin therapy with maintenance were included. Endpoints were recurrence-free survival and progression-free survival.
A total of 231 (19.7%) of patients had T2DM prior to TURB. Five-year recurrence-free survival estimates were 12.5% in patients with T2DM compared to 36% in patients without T2DM, P < 0.0001. Five-year PFS estimates were 60.5% in patients with T2DM compared to 70.2% in patients without T2DM, P = 0.003. T2DM was independently associated with disease recurrence (hazard ratio = 1.41; 95% confidence interval = 1.20–1.66, P < 0.001) and progression (hazard ratio = 1.27; 95% confidence interval = 0.99–1.63, P < 0.001), after adjusting for other known predictive factors such as tumor size, multifocality, T1G3 on re-TURB, body mass index, lymphovascular invasion, and neutrophil-to-lymphocytes ratio.
Given the potential implications for management, prospective validation of this finding along with translational studies designed to investigate the underlying biology of such an association are warranted.

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^☆: Author Contributions: C. B. extracted data, analyzed statistics, analyzed and interpreted data, drafted the manuscript. X. Y. critically reviewed/edited the manuscript for important intellectual content. W.X. contributed to the data interpretation and reviewed/edited the manuscript. H. L., Z. X. and C. S. participated in the study search strategy. X. Q. originated and designed the study, analyzed and interpreted data, and critically reviewed/edited the manuscript for important intellectual content.

^☆☆: Disclosure: No potential conflicts of interest relevant to this article were reported.

^★: Funding: We state that we have not received any funding.

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Diabetes mellitus and incidence and mortality of kidney cancer: A meta-analysis☆,☆☆,★

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Retrieval of studies

Characteristics of the subjects in selected studies

Discussion

European Journal of Cancer

Controlled Clinical Trials

Annals of oncology: Official Journal of the European Society for Medical Oncology / ESMO

Cancer Letters

European Urology

Journal of Biological Chemistry

Journal of Chronic Diseases

Cancer Epidemiology

Annals of Oncology : Official Journal of the European Society for Medical Oncology / ESMO

Pre-existing type-2 diabetes is not an adverse prognostic factor in patients with renal cell carcinoma: A single-center retrospective study

Urologic Oncology

Risk of cancer in a large cohort of U.S. veterans with diabetes. International Journal of Cancer

Journal International du Cancer

Insulin-like growth factors and diabetes

Diabetes/Metabolism Reviews

Long-term all-cause mortality in cancer patients with pre-existing diabetes mellitus: A systematic review and meta-analysis

Journal of the American Medical Association

The association of fasting insulin concentrations and colonic neoplasms in acromegaly: A colonoscopy-based study in 210 patients

Journal of Clinical Endocrinology and Metabolism

Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults

American Journal of Epidemiology

Serum IGF-I, IGF-II, IGFBP-3, and IGF-I/IGFBP-3 molar ratio and risk of pancreatic cancer in the prostate, lung, colorectal, and ovarian cancer screening trial

Cancer epidemiology, biomarkers & prevention: A publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

Bias in meta-analysis detected by a simple, graphical test

BMJ (Clinical research ed)

The evolving diabetes burden in the United States

Annals of Internal Medicine

Diabetes mellitus and risk of endometrial cancer: A meta-analysis

Diabetologia

A case–control study of factors affecting the development of renal cell cancer

American Journal of Epidemiology

Quantitative methods in the review of epidemiologic literature

Epidemiologic Reviews

Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: A cohort study

Diabetologia

Risk of cancer following hospitalization for type 2 diabetes

The Oncologist

Quantifying heterogeneity in a meta-analysis

Statistics in Medicine

Diabetes mellitus and the risk of cancer: Results from a large-scale population-based cohort study in Japan

Archives of Internal Medicine

Fasting serum glucose level and cancer risk in Korean men and women

Journal of the American Medical Association

Global cancer statistics

CA: A Cancer Journal for Clinicians

Diabetes mellitus and incidence and mortality of colorectal cancer: A systematic review and meta-analysis of cohort studies

European Journal of Epidemiology

Type 2 diabetes and the risk of renal cell cancer in women

Diabetes Care