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Betel Nut Chewing Is Associated With The Risk Of Kidney Stone Disease Ⅱ

May 10, 2024

4. Discussion

In this cross-sectional study of a large-scale, community-based representative population in Taiwan, betel nut chewing was significantly associated with KSD after adjustment for confounders. We also found that the more betel nuts chewed daily, the higher the prevalence of KSD. To the best of our knowledge, this is the first large study to demonstrate this association to date. 

Betel nut, the seed of the Areca catechu palm tree, is common in Southern, Southeast Asian, and Pacific island countries [12]. The prevalence of chewing betel nut is estimated as above 10% of the world population [22]. Betel nut is one of the most common addictive natural products on earth [23]. The pernicious effect of betel nut is not just restricted to the oral cavity but also affects systemic health including the central nervous system, cardiovascular disease, metabolic syndrome, type 2 DM, hypertension, dyslipidemia, and chronic kidney disease [16,24–29]. A previous study enrolled eight patients with recurrent urinary stones and discovered the possibility of increased risk of urinary stones in betel nut chewers [30]. There was no control group in this study, which limited the ability to evaluate the odds of KSD between betel nut chewers and non-chewers. Liu et al. conducted a cross-sectional case-control study and found that current betel nut chewers had a higher risk for calcium urolithiasis than non-chewers (OR, 1.97; 95% CI, 1.06 to 3.64) [31]. However, this was a single hospital study with a small cohort (354 cases vs. 354 age- and sex-matched controls), which limited the generalizability of their findings. Our study builds on the results of both studies and confirms the association between betel nut chewing and the risk of KSD by a large population-based study

A strength of our research includes the finding of the dose-response effect between betel nut chewing and the risk of KSD. We observed that subjects with high doses of exposure (>30 betel nuts per day) had a higher risk of KSD compared with those with low-dose exposure. Similar dose-response effects could be found between betel nut consumption and other diseases such as cardiovascular disease [32], metabolic disease [32], and oral cancer [33]. A meta-analysis, which consisted of 17 studies with 388,134 patients, evaluated the impact of chewing betel nut on cardiovascular disease, metabolic disease, and all-cause mortality, with results showing that betel nut not only increased the risk of events but demonstrated significant dose-response relationships as well [32]. Another case-control study examined the dose-response relationships between the risk of oral cancer and lifetime cumulative exposure to betel nuts and observed that the risk of oral cancer rose steeply at low amounts and plateaued at higher exposure to betel nuts [33]. In line with these studies, we also observed dose-response effects between betel nut chewing and the risk for KSD.

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The mechanism that links chewing betel nut with KSD remains unclear, although the potential mechanisms might be related to the renal damage caused by arecoline, which is a major component of alkaloids in betel nut. Previous studies have shown that arecoline could increase oxidative stress and cause DNA damage in vitro and in vivo [34–36]. Furthermore, Hsieh et al. found that arecoline could promote morphological changes and migration in human kidney (HK2) cells and could induce epithelial-mesenchymal transition (EMT) and subsequent renal fibrosis by upregulating the expression of N-cadherin, vimentin, α-SMA and collagen [37]. These findings suggest that arecoline is associated with renal dysfunction and can cause chronic injury to the kidney [37]. An animal study also showed that rats fed with betel nuts had higher percentages of kidney tubular injury than those without [38]. Kidney stone formation is proposed to be related to the damage of renal tubule epithelial cells and renal fibrosis [39–41]; additionally, increased oxidative stress plays a major role in the deposition of urinary crystals in the renal tubules during stone formation [42]. Taken together, betel nut and its components may increase oxidative reaction, cause renal injury, and eventually, stone formation.

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According to the International Agency for Cancer Research (IARC) and the specialized cancer agency of the World Health Organization (WHO), betel nut has been classified as a group 1 carcinogen. Betel nut is also associated with multiple health-harming effects, including the kidney [29,43]. Unfortunately, despite the adverse effects of betel nuts, there is a lack of global policy to control the use of betel nuts [44]. 

The Taipei city government, the capital of Taiwan, once proposed a regulation: "Betel Nut Hygiene Management Autonomy Provision," which aimed to prohibit chewing betel nuts in public places, but it failed eventually due to opposition from betel nut users, growers, and retailers [45]. Until now, it can only add warnings on the packaging of betel nuts and educate the public about the hazards of chewing betel nuts, but any supposed beneficial effects still need further research [46]. Through our study, we hope to remind the government and the public about the potential harm of betel nuts and further reduce demand.

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To the best of our knowledge, this study is the first, large-scale, multiple-covariate, and community-based one with more than 43,000 subjects investigating the association between betel nut chewing and KSD. Additionally, the frequency of betel nut use per day was also analyzed to investigate the dose-response effect. Despite these strengths, there are some limitations. Firstly, the major limitation is the use of self-reported diagnosed KSD instead of medical records or image-confirmed KSD; however, in such large-scale research, it is difficult to review every medical record and image. Such alternative methods have been widely used in large studies, such as the UK Biobank and Biobank Japan. In addition, the self-reported diagnosis of KSD by the subjects represents the clinical significance of the disease, rather than asymptomatic or incidental diseases. Secondly, a causal relationship could not be confirmed in this cross-sectional study. Thirdly, all the

subjects come from Taiwan, and no other people from different countries were included, which might limit the generalizability of our findings. Fourthly, future studies are required to include other dietary habits or daily fluid-amount intake for evaluation. 


5. Conclusions

Our study demonstrates that not only hypertension, DM, dyslipidemia, gout, and obesity but also betel nut chewing are strongly associated with KSD. With an increase in the daily intake of betel nut, the risk of KSD also increased. This implies that reducing the population of betel nut users could improve men's health and further attention to this problem is warranted. 

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Supplementary Materials: The following supporting information can be downloaded at https: //www.mdpi.com/article/10.3390/jpm12020126/s1, Table S1: Relative risk for kidney stone disease in a subgroup analysis for subjects without a history of hypertension, DM, dyslipidemia, gout, and obesity (BMI ≥ 30 kg/m2 ) (N = 28,481).


Author Contributions: Conceptualization, C.-K.C., C.-F.C., Y.-C.L., J.-H.J., H.-S.W., J.-T.S., Y.-H.T.and J.-H.G.; methodology, C.-K.C. and J.-H.G.; software, J.-H.G.; validation, J.-H.G.; formal analysis,J.-I.L. and J.-H.G.; investigation, J.-H.G.; resources, S.-P.H. and J.-H.G.; data curation, C.-K.C., S.-P.H.and J.-H.G.; writing-original draft preparation, C.-K.C. and J.-H.G.; writing-review and editing,C.-K.C. and J.-H.G.; visualization, C.-K.C. and J.-H.G.; supervision, J.-H.G.; project administration,J.-H.G.; funding acquisition, None. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Kaohsiung Medical University Hospital (KMU-HIRB-E(I)-20190398).

Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Written informed consent has been obtained from the patients to publish this paper.

Data Availability Statement: Restrictions apply to the availability of these data. Data was obtained from Taiwan Biobank and are available with the permission of Taiwan Biobank.

Acknowledgments: This work was supported partially by the Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan, by Kaohsiung Medical University Research Center Grant (KMU TC109A01-1) and by Kaohsiung Municipal Siaogang Hospital (S-108-017).

Conflicts of Interest: The authors declare no conflict of interest. 


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