Diabetes and kidney cancer: A direct or indirect association?

A positive association between diabetes and kidney cancer has been reported in several investigations, but it is unclear whether diabetes or its complications account for this association. Recent advances in estimating direct associations may be useful for elucidating the association between diabetes and kidney cancer. Therefore, we performed a case-control analysis to evaluate whether the direct association between diabetes and kidney cancer is the primary concern in this exposure-outcome relation. Discharge data (with International Classification of Diseases – 9 codes) from 2001 for hospitals throughout Florida were used to construct a case-control population of inpatients aged ≥45 years. Cases (n=1,909) were inpatients with malignant kidney cancer and controls (n=6,451) were inpatients with motor vehicle injuries. Diabetes status was ascertained for cases and controls. Covariates that required adjustment to estimate the total (age, gender, ethnicity, obesity, and smoking) and direct (age, gender, ethnicity, obesity, smoking, hypertension, and kidney disease) associations were identified in a directed acyclic graph. Binary logistic regression was used to estimate the adjusted total and direct odds ratios (ORs) and corresponding 95% confidence intervals (CIs) of kidney cancer for diabetics. The odds of kidney cancer were higher for inpatients with diabetes than inpatients without diabetes when estimating the total association (OR=1.27, 95%CI: 1.10, 1.47) but attenuated when estimating the direct association (OR=1.08, 95%CI: 0.93, 1.25). Our findings provide preliminary insight that the direct association between diabetes and kidney cancer may not be the primary concern in this exposure-outcome relation; indirect pathways (i.e. diabetic complications) may have greater influence on this relation. A similar analysis using longitudinal data with appropriately measured covariates may provide more definitive conclusions and could have implications for kidney cancer prevention among diabetics

PBRM1 acts as a p53 lysine-acetylation reader to suppress renal tumor growth.

p53 acetylation is indispensable for its transcriptional activity and tumor suppressive function. However, the identity of reader protein(s) for p53 acetylation remains elusive. PBRM1, the second most highly mutated tumor suppressor gene in kidney cancer, encodes PBRM1. Here, we identify PBRM1 as a reader for p53 acetylation on lysine 382 (K382Ac) through its bromodomain 4 (BD4). Notably, mutations on key residues of BD4 disrupt recognition of p53 K382Ac. The mutation in BD4 also reduces p53 binding to promoters of target genes such as CDKN1A (p21). Consequently, the PBRM1 BD4 mutant fails to fully support p53 transcriptional activity and is defective as a tumor suppressor. We also find that expressions of PBRM1 and p21 correlate with each other in human kidney cancer samples. Our findings uncover a tumor suppressive mechanism of PBRM1 in kidney cancer and provide a mechanistic insight into the crosstalk between p53 and SWI/SNF complexes

Patients With Kidney Cancer

To develop a preoperative prognostic model in order to predict recurrence-free survival in patients with nonmetastatic kidney cancer.A multi-institutional data base of 1889 patients who underwent surgical resection between 1987 and 2007 for kidney cancer was retrospectively analyzed. Preoperative variables were defined as age, gender, presentation, size, presence of radiological lymph nodes and clinical stage. Univariate and multivariate analyses of the variables were performed using the Cox proportional hazards regression model. A model was developed with preoperative variables as predictors of recurrence after nephrectomy. Internal validation was performed by Harrells concordance index.The median follow-up was 23.6 months (1222 months). During the follow-up, 258 patients (13.7) developed cancer recurrence. The median follow-up for patients who did not develop recurrence was 25 months. The median time from surgery to recurrence was 13 months. The 5-year freedom from recurrence probability was 78.6. All variables except age were associated with freedom from recurrence in multivariate analyses (P 0.05). Age was marginally significant in the univariate analysis. All variables were included in the predictive model. The calculated c-index was 0.747.This preoperative model utilizes easy to obtain clinical variables and predicts the likelihood of development of recurrent disease in patients with kidney tumors

Gallstones, cholecystectomy and kidney cancer: observational and Mendelian randomisation results based on large cohorts.

BACKGROUND AND AIMS Gallstones (cholelithiasis) constitute a major health burden with high costs related to surgical removal of the gallbladder (cholecystectomy), generally indicated for symptomatic gallstones. The association between gallstones, cholecystectomy and kidney cancer is controversial. We comprehensively investigated this association, considering age at cholecystectomy and time from cholecystectomy to kidney cancer diagnosis, and assessing the causal effect of gallstones on kidney cancer risk by Mendelian randomisation (MR). METHODS We compared the risk of kidney cancer in cholecystectomised and non-cholecystectomised individuals (16.6 million in total) from the Swedish nationwide cancer, census, patient and death registries using hazard ratios (HRs). For two-sample and multivariable MR, we used summary statistics based on 408,567 UK Biobank participants. RESULTS During a median follow-up of 13 years, 2,627 of 627,870 cholecystectomised Swedish patients developed kidney cancer (HR=1.17, 95% CI 1.12-1.22). Kidney cancer risk was particularly increased in the first 6 months after cholecystectomy (HR=3.79, 95% CI 3.18-4.52) and in patients cholecystectomised before age 40 (HR=1.55, 95% CI 1.39-1.72). MR results based on 18.417 gallstone and 1,788 kidney cancer patients from the UK revealed a causal effect of gallstones on kidney cancer risk (9.6% risk increase per doubling in gallstone prevalence, 95% CI 1.2%-18.8%). CONCLUSIONS Both observational and causal MR estimates based on large prospective cohorts support an increased risk of kidney cancer in gallstone patients. Our findings provide solid evidence for the compelling need to diagnostically rule out kidney cancer before and during gallbladder removal, to prioritise kidney cancer screening in patients undergoing cholecystectomy in their 30s, and to investigate the underlying mechanisms linking gallstones and kidney cancer in future studies

"Mortality trends and geographic distribution of kidney cancer in Peru: a secondary analysis"

"Background The incidence of kidney cancer has been increasing worldwide, with variable patterns in mortality due to improved diagnostic techniques and increased survival. The mortality rates, geographical distribution and trends of kidney cancer in South America remain poorly explored. This study aims to illustrate mortality by kidney cancer in Peru. Methods A secondary data analysis of the Deceased Registry of the Peruvian Ministry of Health database, from 2008 to 2019 was conducted. Data for kidney cancer deaths were collected from health facilities distributed throughout the country. We estimated age-standardized mortality rates (ASMR) per 100,000 persons and provided an overview of trends from 2008 to 2019. A cluster map shows the relationships among 3 regions. Results A total of 4221 deaths by kidney cancer were reported in Peru between 2008 and 2019. ASMR for Peruvian men ranged from 1.15 to 2008 to 1.87 in 2019, and from 0.68 to 2008 to 0.82 in 2019 in women. The mortality rates by kidney cancer rose in most regions, although they were not significant. Callao and Lambayeque provinces reported the highest mortality rates. The rainforest provinces had a positive spatial autocorrelation and significant clustering (p<0.05) with the lowest rates in Loreto and Ucayali. Conclusion Mortality by kidney cancer has increased in Peru, being a trend that disproportionally affects more men than women. While the coast, especially Callao and Lambayeque, present the highest kidney cancer mortality rates, the rainforest has the lowest rates, especially among women. Lack of diagnosis and reporting systems may confound these results.

The blood metabolome of incident kidney cancer: A case-control study nested within the MetKid consortium.

BackgroundExcess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI).Methods and findingsWe assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case-control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 × 10-8). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 × 10-5), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some-but not all-metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., -0.17 SD change [ßBMI] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 × 10-5). BMI was also associated with increased levels of glutamate (ßBMI: 0.12, p = 1.5 × 10-3). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds.ConclusionsThis study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI-the principal modifiable risk factor of kidney cancer

Public attitudes towards screening for kidney cancer: an online survey

Funder: Kidney Cancer UKFunder: The Urology FoundationAbstract: Background: Kidney cancer is often asymptomatic, leading to proposals for a screening programme. The views of the public towards introducing a new screening programme for kidney cancer are unknown. The aim of this study was to explore attitudes towards kidney cancer screening and factors influencing intention to attend a future screening programme. Methods: We conducted an online population-based survey of 1021 adults aged 45–77 years. The main outcome measure was intention to attend four possible screening tests (urine, blood, ultrasound scan, low-dose CT) as well as extended low-dose CT scans within lung cancer screening programmes. We used multivariable regression to examine the association between intention and each screening test. Results: Most participants stated that they would be ‘very likely’ or ‘likely’ to undergo each of the screening tests [urine test: n = 961 (94.1%); blood test: n = 922 (90.3%); ultrasound: n = 914 (89.5%); low-dose CT: n = 804 (78.8%); lung CT: n = 962 (95.2%)]. Greater intention to attend was associated with higher general cancer worry and less perceived burden/inconvenience about the screening tests. Less worry about the screening test was also associated with higher intention to attend, but only in those with low general cancer worry (cancer worry scale ≤ 5). Compared with intention to take up screening with a urine test, participants were half as likely to report that they intended to undergo blood [OR 0.56 (0.43–0.73)] or ultrasound [OR 0.50 (0.38–0.67)] testing, and half as likely again to report that they intended to take part in a screening programme featuring a low dose CT scan for kidney cancer screening alone [OR 0.19 (0.14–0.27)]. Conclusion: Participants in this study expressed high levels of intention to accept an invitation to screening for kidney cancer, both within a kidney cancer specific screening programme and in conjunction with lung cancer screening. The choice of screening test is likely to influence uptake. Together these findings support on-going research into kidney cancer screening tests and the potential for combining kidney cancer screening with existing or new screening programmes

The therapeutic aspects of the endocannabinoid system (ECS) for cancer and their development: from nature to laboratory

The endocannabinoid system (ECS) is a group of neuromodulatory lipids and their receptors, which are widely distributed in mammalian tissues. ECS regulates various cardiovascular, nervous, and immune system functions inside cells. In recent years, there has been a growing body of evidence for the use of synthetic and natural cannabinoids as potential anticancer agents. For instance, the CB1 and CB2 receptors are assumed to play an important role inside the endocannabinoid system. These receptors are abundantly expressed in the brain and fatty tissue of the human body. Despite recent developments in molecular biology, there is still a lack of knowledge about the distribution of CB1 and CB2 receptors in the human kidney and their role in kidney cancer. To address this gap, we explore and demonstrate the role of the endocannabinoid system in renal cell carcinoma (RCC). In this brief overview, we elucidate the therapeutic aspects of the endocannabinoid system for various cancers and explain how this system can be used for treating kidney cancer. Overall, this review provides new insights into cannabinoids' mechanisms of action in both in vivo and in vitro models, and focuses on recent discoveries in the field

Declining mortality from kidney cancer in Europe

Mortality rates from kidney cancer increased throughout Europe up until the late 1980s or early 1990s. Trends in western European countries, the European Union (EU) and selected central and eastern European countries have been updated using official death certification data for kidney cancer abstracted from the World Health Organisation (WHO) database over the period 1980-1999. In EU men, death rates increased from 3.92 per 100 000 (age standardised, world standard) in 1980-81 to 4.63 in 1994-95, and levelled off at 4.15 thereafter. In women, corresponding values were 1.86 in 1980-81, 2.04 in 1994-95 and 1.80 in 1998-99. Thus, the fall in kidney cancer mortality over the last 5 years was over 10% for both sexes in the EU. The largest falls were in countries with highest mortality in the early 1990s, such as Germany, Denmark and the Netherlands. Kidney cancer rates levelled off, but remained very high, in the Czech Republic, Baltic countries, Hungary, Poland and other central European countries. Thus, in the late 1990s, a greater than three-fold difference in kidney cancer mortality was observed between the highest rates in the Czech Republic, the Baltic Republics and Hungary, and the lowest ones in Romania, Portugal and Greece. Tobacco smoking is the best recognised risk factor for kidney cancer, and the recent trends in men, mainly in western Europe, can be related to a reduced prevalence of smoking among men. Tobacco, however, cannot account for the recent trends registered in wome