Kidney stones (KS) are widespread diseases of the urinary system, that clinically manifest as hematuria, renal colic, urinary tract infection, urinary tract obstruction, and, in severe cases may manifest as renal failure and are even life-threatening (1–3). Epidemiological studies show that KS diseases affect 1% to 20% of the population worldwide and the annual incidence of new cases is approximately 150-200 per 100,000 people, 25% of whom require hospitalization (2, 4, 5). Unfortunately, the prevalence of KS is on the rise worldwide and with a stone recurrence rate up to over 50% within five years (3, 6). To date, KS diseases have become a major public health problem, causing a serious economic burden to individuals and the country (7, 8). Therefore, how to prevent the occurrence of KS should be regarded as a high priority.

Currently, accumulated evidence suggests that metabolic syndrome (MS) is implicated in an elevated risk of KS (9–11), in which the role of obesity has attracted more attention from researchers (12, 13). Obesity has emerged as a public health problem in many countries worldwide (14, 15). A study conducted by Carbone et al. (16) showed that the prevalence of obesity in patients with KS was approximately 10-35%. Consistent with this, a higher rate of KS was also found in obese (11.2%) and overweight populations (9.1%) than in normal weight populations (6.1%) (17). Moreover, the risk of KS increased markedly with increasing body mass index (BMI) (18, 19). Although obesity was strongly associated with KS, reliable indicators of obesity to predict the risk of KS presence are extremely lacking.

Interestingly, researchers have recognized that adipose tissue has complex functions and that not all adipose tissue is harmful to the body, such as brown fat (20), so that high body weight and overall excess adiposity cannot simply be assumed to be poor health states. Therefore, defining and quantifying lipid accumulation in specific settings that may represent certain physiological risks can contribute to a deeper understanding of the role of adipose tissue in the pathophysiological processes of disease and its value in predicting the risk of disease occurrence. Several studies have shown that visceral adipose tissue is more strongly associated with diabetes, hypertension, cardiovascular disease and cardiometabolic risk factors than subcutaneous adipose tissue (21–25). However, traditional indicators of obesity, such as waist circumference (WC), BMI, waist-to-hip ratio, and waist-to-height ratio, did not differentiate visceral fat from subcutaneous fat. Although CT or MRI is considered the gold standard for the quantification of abdominal obesity, its expensive, complex and radiation-risky nature has prevented its large-scale implementation.

The visceral adiposity index (VAI) is an indicator of abdominal fat distribution and adipose tissue function proposed by Amato et al. (26). Its calculation includes not only anthropometric characteristics such as WC and BMI but also two metabolic indicators, triglycerides (TGs) and high-density lipoprotein cholesterol (HDL-C). These metrics and metabolism are strongly associated with the development of KS (18, 27) which allows us to more accurately assess the relationship between obesity and KS. Thus, we propose the hypothesis that VAI is associated with the risk of kidney stones. To explore this hypothesis, we investigated the link between VAI and KS diseases based on data from 29384 individuals.

Although obesity is involved in the high prevalence of KS (11, 19, 27), reliable indicators of obesity to predict the risk of KS remain lacking. In this study, based on the NHANES database we demonstrated that a higher VAI was linked to a higher prevalence of KS in the representative U.S. adults after adjusting for confounders and the prevalence of KS increases by 13% for each unit of VAI increment after normalizing the VAI by LN transformation. Moreover, by converting the VAI from a continuous variable to a trichotomous categorical variable, sensitivity analysis showed that the VAI was reliable, with a significantly greater incidence of KS in the highest VAI group (Tertile 3). We also discovered that VAI was linearly related to KS presence in the dose response and threshold effect analyses. Our findings suggest that VAI may be a promising predictor of KS.

VAI as a specific index of visceral adiposity disorders has been widely associated with cardiovascular diseases, hypertension, human purine metabolism, insulin resistance and thyroid function (30–32). Recently, a retrospective study reported by Sönmez et al. (33) concluded that the VAI was positively correlated with the creatinine levels in patients with KS. However, evidence regarding the association between the VAI and KS are limited. In a retrospective study of 1,698 patients with stones, Trinchieri et al. (34) found that overweight and obese patients were commonly associated with increased excretion of urinary calcium, urinary oxalate and uric acid, which are strongly associated with the development of KS (3). Excessive visceral adipose tissue can lead to disorders of fatty acid metabolism and release free fatty acids, which induce inflammatory responses in a variety of cells such as macrophages and adipocytes (35, 36). Taguchi et al. (12) reported that mice treated with a high-fat diet exhibited increased accumulation of lipids in the kidney and triggered an inflammatory response, which ultimately led to the development of kidney stones. Although the above reports do not directly point to the relationship between VAI and KS, there may be a link between visceral adiposity and KS, which may be an idea to explain the better development of KS in patients with a high VAI.

KS is a common urological disease with a high global prevalence but an unknown mechanism. On the one hand, the specific mechanism of its occurrence is still unclear, and there is no effective etiologic prevention method; on the other hand, the treatment method of KS is constantly adjusted according to the progress of the patient’s stones, and early detection of KS can reduce the possibility of invasive operations for patients, reduce the pain suffered by patients and reduce the cost of treatment (37). Therefore, secondary prevention in the high-risk group is particularly important to achieve early detection, diagnosis, and treatment of KS. Our study showed that a high VAI is a statistically significant risk factor associated with KS. The VAI is related to the volume and area of visceral adipose tissue and is an index to evaluate the extent of visceral fat distribution and accumulation. Moreover, the VAI has higher sensitivity and specificity than traditional indicators such as waist circumference, BMI, and blood lipids (26). Our study supports that an elevated VAI was significantly associated with KS. Screening for VAI in high-risk groups provides new ideas for prevention and treatment of KS, which can prevent the occurrence of KS and provide early management of patients with KS.

Subgroup analysis showed that the relationship between the VAI and KS incidence was robust and generalized, and this positive correlation still existed in different gender, ethnicities, and age groups. This result needs to be supported by a larger sample size study. After further subgroup studies, the lowest VAI group (Tertile 1) showed a significant 25% increase in the prevalence of KS compared with the highest VAI group (Tertile 3), reflecting the considerable sensitivity of the VAI. A promising point in this study was that in different age subgroups, patients with a high VAI in the younger age group had a stronger correlation with KS presence than patients with a high VAI in the older age group, which gives us a new strategy for KS prevention, namely the management and control of the VAI in younger patients. We hypothesized that an elevated VAI is an important factor in the development of pro-KS and contributes to cardiovascular disease, metabolic syndrome and other disorders. However, the low age of the patient itself is a protective factor for cardiovascular disease, metabolic syndrome but has no significant protective effect on the development of KS, so the prediction of KS by the high VAI may have a higher specificity within younger individuals. No relevant reports in this regard have been published, and follow-up large-scale prospective studies are needed to confirm this causal relationship.

Our study has the following advantages. First, NHANES study participants are representative U.S. adults, which closely followed a well-designed study protocol with extensive guarantee and conformance. Second, we controlled for confounding variables and performed subgroup analyses to make our findings reliably and stably applicable to a wider range of individuals. Third, we further demonstrated that the VAI was linearly related to the prevalence of KS. However, the limitations of our study cannot be ignored. First, our cross-sectional investigation was based on the NHANES database, which prevented us from assessing a causal relationship between VAI and KS. Second, the prevalence of KS was obtained from patient self-reports, and recall bias was inevitable. Despite these limitations, our study clearly revealed a positive correlation between the VAI and KS presence.

We demonstrated that the elevated VAI was strongly associated with KS in representative U.S. adults in a cross-sectional study. VAI may be a promising indicator for the risk of KS, which is beneficial for prevention guidance of KS.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the NCHS Research Ethics Review Committee approved the NHANES survey protocol (https://www.cdc.gov/nchs/nhanes/irba98.htm). The patients/participants provided their written informed consent to participate in this study.

ZH, MC and JX: Conceptualization, Methodology and Project administration; BH, QH and XS: Visualization, Investigation, Software and Writing - review & editing; YC, YX: Software and data collection. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

This study was supported by the National Natural Science Foundation of China (82070724, 82000672) and the Natural Science Foundation of Anhui Province (1908085MH246, 2108085MH269).

We thank all other researchers in our laboratory for their valuable help in our work.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.