The kidney stone is a benign disease that affects the renal calyces, renal pelvis, and the junction of the renal pelvis and ureter and is one of the most common in urology (1). Current prevalence levels of kidney stones are high, and they have been increasing globally throughout the past few decades (2). According to the most recent survey study of the National Health and Nutrition Examination Survey (3), the prevalence of kidney stones is as high as 11% in the United States, 9% in Europe (1),and 5.8% in China (4). Presently, minimally invasive endoscopic procedures such as percutaneous nephrolithotomy, flexible ureteroscopic lithotripsy and other endoscopic procedures are routinely used to treat kidney stones.A high recurrence risk exists even after completion of treatment (5). If not effectively treated, it may result in serious complications such as irreversible kidney damage and end-stage renal disease.It is becoming increasingly apparent that kidney stones are a significant public health concern, as well as a major economic burden for the healthcare system (6).

As a result of the high rates of recurrence and incidence of kidney stones, prevention should be considered a high priority.A multitude of systemic factors have been reported to be associated with an increased risk of kidney stones, suggesting that genetic, environmental, and nutritional influences may play an important role in stone development (7). It has become increasingly apparent that modifiable factors, including diet and lifestyle, can influence kidney stone development. Every time the conditions of living improve, the number of people suffering from metabolic syndrome increases due to high-fat and high-sugar diets. Metabolic syndrome (MetS) refers to a group of metabolic disorders, which include obesity (primarily abdominal obesity), fasting, postprandial hyperglycemia, hypertension, and dyslipidemia. It has been suggested that these conditions may be linked to a common mechanism: insulin resistance(IR) (8, 9). Increasingly, studies confirm an association between IR and major kidney stones. It is believed that IR increases the risk of urinary calcium stones by reducing the excretion of citrate in the urine (10). Metabolic syndrome components may contribute to the development of kidney stones through subclinical hyperinsulinemia and insulin resistance (11).

Hyperinsulinemic normoglycemic clamps (HECs) are currently the gold standard for assessing insulin sensitivity in peripheral tissues (12). Due to the complexity, time consuming nature, and resource consuming nature of this method, simpler metrics are often used to assess insulin resistance. The METS-IR index, a new metric for measuring insulin resistance (IR) as a simple, reliable, and reproducible predictive metric, has been proposed in 2018 (12, 13). Given the METS-IR index’s role as a marker for IR, a possible correlation between the METS-IR index and renal calculi might be posited. Nevertheless, no previous study has investigated the relationship between the METS-IR index and kidney stones. Therefore, in the present study, we aimed to assess the value of the METS-IR index in the incidence of kidney stones in the United States (US) population.

An overview of the baseline demographic characteristics of the participants is provided in Table 1 . There was a significant difference in the METS-IR index between the stone and non-stone groups, 47.291 ± 13.591vs 43.259 ± 12.936, p< 0.001.

Generally, kidney stones are a recurrent disease over the course of a lifetime. Recurrent stones are more likely to recur in the future and have a poorer prognosis (7).A low urine output, a high urinary calcium level, a high urinary uric acid level, a high oxaluria level, and an abnormal urinary pH level can all contribute to stone formation (20).Due to the complex etiology of stones, large individual differences, regional differences, and high recurrence rates, a comprehensive study of risk factors for stones and the search for factors associated with stone recurrence are necessary to guide treatment and prevention.

As far as our knowledge is concerned, this is the first study to investigate the relationship between the METS-IR index and kidney stones and to demonstrate the predictive significance of METS-IR in the development of kidney stones. The results of this large cross-sectional study reveal that higher METS-IR scores are positively associated with an increased risk of kidney stone formation. Individuals in the highest tertile of METS-IR had a 0.59-fold greater risk of developing new kidney stones as compared to those in the lowest tertile. Moreover, this study not only evaluated the independent effects of METS-IR and the risk of kidney stone development, but also examined the dose–response relationship between the two factors and derived a threshold effect for METS-IR of 59.8314.In comparison to the left side of the inflection point, when METS-IR was at 59.8314, there was an increasing trend in kidney stone occurrence with increasing METS-IR (OR =1.0238, 95% CI: 1.0178-1.0299); however, when METS-IR was at 59.8314, the trend gradually plateaued compared to the right side of the inflection point (OR =1.0015, 95% CI. 0.9957-1.0073).The factors included in this study were stratified by sex, age, hypertension, and diabetes status, while the interaction test p-values were not statistically significant, indicating that this association was independent of age, hypertension, and diabetes, suggesting that it could be applied to all types of populations. Intriguingly, our results suggest that an elevated METS-IR index is associated with a greater risk of kidney stone formation among non-hypertensive and non-diabetic individuals than among hypertensive and diabetic individuals. First, the possibility exists that those with diabetes and hypertension may be more cognizant of healthy eating, after all, a high sugar diet is more likely to contribute to the development of metabolic syndrome (21, 22). In addition, Iran found that non -hypertensive people`s IR resistance will cause cardiovascular disease, and there is no such effect in people with hypertension (23). Another Japanese study found that the increase in IR levels in non -diabetic people will lead to increasing coronary heart disease and stroke probability (24). Hedblad et al. (25) reported that the HOMAIR distribution of non-diabetic individuals has the 75th percentage value (2.12 for men, 1.80 (for women). The risk of infarction is significantly higher than those without these HOMA-IR values.These results suggest that IR resistance is more likely to cause more severe consequences in non-diabetic and non-hypertensive populations. Although the research objects are different, this result also confirms to some extent that our results may be correct. Considering these findings, it is also suggested that the association between METS-IR index and kidney stones should be more closely monitored among healthy people.

The METS-IR index was first reported in 2018 and is considered to be an intuitive and reliable measure of inflammation that can be used in clinical decision making (12, 13). In a cohort study conducted in Korea, Kim et al. demonstrated that IR was associated with the development of kidney stones in Korean men (26). Another study from Japan also confirmed that metabolic syndrome can cause insulin resistance, which in turn increases the risk of kidney stones (11). There has been some research on the influence of IR on kidney stone formation as well. Insulin resistance has been shown to cause ammonia production to decline and sodium and bicarbonate reabsorption to increase, which results in a decrease in the pH of the urine (27). Likewise, insulin resistance may result in a reduction in renal ammonia production, which will lead to a reduction in ammonia buffering and further decrease urine pH (28). In urine with a pH below 5.5, less soluble uric acid is formed from urate, which can cause uric acid stones (29). Further, IR increases renal tubule citrate uptake and decreases urinary citrate levels (10), which is one of the primary causes of calcium stones. In light of the fact that METS-IR index and IR levels are positively correlated, it may be possible to explain why a higher METS -IR index is related to an increased risk of kidney stones.

Several advantages are associated with our study. The NHANES is a representative sample of the US population. It strictly adheres to a well-designed study protocol with high standards of quality assurance and quality control. Moreover, our results are robust when tested against a range of sensitivity analyses that confirm our primary analysis. Nonetheless, we recognize the limitations of our study. As a result of using the NHANES database, a cross-sectional study, we were not able to investigate a causal relationship between METS-IR and kidney stones. Additionally, the diagnosis of kidney stones was made on the basis of a questionnaire, which was unable to provide information on the size and type of kidney stones, and was susceptible to recall bias; and finally, detailed clinical variables, such as medication history and kidney stone type, were not included in the database and required further investigation. Upon confirmation of our findings, an RCT study in a multicenter environment will be conducted. In spite of these limitations, this study has the strength of suggesting a new index of kidney stone incidence and demonstrating the relationship between METS-IR scores and kidney stones.

According to the results of this cross-sectional analysis of a representative sample, a high METS-IR index is associated with an increase in the prevalence of kidney stones. Mets-IR shows promise as a new marker that can help guide prevention of kidney stones

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material.

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.

XS, YangC, YanC, HL, and GL performed the material preparation, collected the data, and analyzed the data. ZH wrote the original draft of the manuscript. All authors contributed to the study conception and design and commented on the previous versions of the manuscript, and read and approved the final manuscript.

This work was supported by the National Natural Science Foundation of China (82070724), Natural Science Foundation of Anhui Province(1908085MH246).

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.

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