Visceral adipose tissue and nephrolithiasis risk: Evidence from National Health and Nutrition Examination Survey and Mendelian randomization analysis

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Visceral adipose tissue and nephrolithiasis risk: Evidence from National Health and Nutrition Examination Survey and Mendelian randomization analysis

https://doi.org/10.21203/rs.3.rs-3902291/v1

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Background: This study aimed to investigate the dose‒response association and potential causal effect between VAT volume and nephrolithiasis risk.

Methods: Multivariable logistic regression models were used to estimate the association between nephrolithiasis risk and VAT quartiles. Restricted cubic splines (RCSs) were employed to investigate potential nonlinear associations between visceral adipose tissue (VAT) and the likelihood of developing nephrolithiasis. A Mendelian randomization analysis was conducted to assess the causal relationship between VAT volume and nephrolithiasis risk.

Results: Participants in the highest VAT quartile demonstrated a significantly greater risk of nephrolithiasis than did those in the lowest quartile across all the models: crude mode (OR [95% CI], 3.00 [1.78, 5.07]), model 1 (OR [95% CI], 2.24 [1.28, 3.92]), model 2 (OR [95% CI], 2.18 [1.24, 3.83]), and model 3 (OR [95% CI], 1.95 [0.99, 3.82]). The RCS analysis revealed a linear relationship between VAT volume and nephrolithiasis (P-nonlinear=0.443). Mendelian randomization analysis provided consistent evidence that higher VAT volume was causally associated with increased nephrolithiasis risk (OR [95% CI], 1.03 [1.02, 1.04]; P<0.001).

Conclusions: This study demonstrated a positive linear causal association between VAT volume and nephrolithiasis risk.

Health sciences/Diseases/Metabolic disorders

Health sciences/Diseases/Urogenital diseases

Nephrolithiasis, commonly known as kidney stones, are common recurrent kidney conditions that are a significant public health concern. Considerable attention has been given to the high prevalence and costs associated with nephrolithiasis¹. Studies have shown that the prevalence of nephrolithiasis has increased to 8.8% in North America ². Given the substantial negative impacts of nephrolithiasis on both society and individuals, identifying modifiable risk factors is crucial for developing effective interventions to reduce the burden of this widespread health problem. Numerous factors, including age, sex, race, obesity, cardiovascular disease, and metabolic changes, have been implicated in the development of nephrolithiasis^2–4.

Among these factors, obesity is a significant and modifiable contributor to nephrolithiasis formation. However, the literature on the association between obesity and nephrolithiasis is limited. Specifically, the assessment of obesity in previous studies was primarily based on body mass index (BMI), which might not accurately distinguish between adipose tissue and nonadipose tissue ⁵. The VAT, referring to the fat located within the abdominal cavity and surrounding organs, has been increasingly linked to various health conditions, including nephrolithiasis ^6–9. Nevertheless, the majority of studies on the association between obesity and nephrolithiasis have utilized less representative samples ¹⁰. Additionally, the dose‒response relationship between VAT and nephrolithiasis remains unclear. Retrospective studies are prone to confounding factors and interference from reverse causality ^11,12.

To address these limitations, we utilized data from the National Health and Nutrition Examination Survey (NHANES), which provides a representative sample of the U.S. population. Furthermore, we employed Mendelian randomization (MR) analysis to investigate the causal relationship between VAT and nephrolithiasis. MR analysis utilizes genetic variation obtained from large-scale genome-wide association studies (GWASs) as an instrumental variable, effectively avoiding confounding factors and reverse causal relationships present in observational studies.¹³

The primary objective of this study was to investigate the association, particularly the dose‒response relationship, between VAT and nephrolithiasis using data from the NHANES. We aimed to determine any potential causal relationship between VAT and nephrolithiasis. By employing Mendelian randomization analysis, we aimed to provide further insights into the mechanisms underlying the observed associations.

Observational study

Data sources and participants

This cross-sectional study utilized data collected during the 2011–2018 cycle of the NHANES, a nationally representative survey that focuses on the noninstitutionalized population of the U.S. Approval for the study was obtained from the Ethics Review Board of the National Center for Health Statistics. The research encompassed a total of 8,570 samples.

Collection and definition of variables

The primary outcome of this observational study was to determine whether individuals had a history of nephrolithiasis. Specifically, participants who answered "yes" to the question "Have you/Has sample person (SP) ever had kidney stones?" identified in the NHANES questionnaire.

The primary exposure factor was visceral adipose tissue (VAT). To assess this possibility, dual-energy X-ray scans were obtained from all eligible participants aged 8–59 years who met the inclusion criteria and had no contraindications as part of the NHANES study. Hologic APEX software was used to define VAT in the scan analysis. The VAT volume, which refers to the amount of fat located inside the abdominal cavity, was measured at the approximate interspace between the L4 and L5 vertebrae.

The researchers also considered various covariates, including age; gender (male or female); race (Mexican American, Other Hispanic, Non-Hispanic White Black, Non-Hispanic Black or Others); education level (less than 9th grade, 9–11th grade, high school graduate/General Educational Development or equivalent, some college or Associate of Arts degree, or college graduate or above); marital status (married, widowed, divorced, separated, never married or living with partner); family PIR (PIR = ratio of family income to poverty threshold) < 1.3, 1.3–3.5, > 3.5); body mass index (BMI, normal or low weight; overweight, Obese); total cholesterol (TC, mg/dL); HDL-Cholesterol (HDL, mg/dL); hypertension (NO or YES); diabetes (NO,Borderline or YES); alcohol (NO or YES);Smoke( Never, smoke (Never, Former or Current); subcutaneous adipose tissue (SAT); and total abdominal adipose tissue (TAT).

Statistical analysis

Sample weights were adjusted to present nationally representative estimates in all analyses according to the stratified, multistage probability sampling design. Continuous variables are presented as the mean ± standard error, while categorical variables are presented as frequencies (percentages). Differences between groups for continuous and categorical variables were calculated using the weighted t test and chi-square test (χ2), respectively.

To control for potential confounding variables, VAT was categorized into quarters and treated as both a continuous variable and a categorical variable. Multivariate logistic regression was conducted with or without adjustment for possible confounding variables to further explore the association between VAT and nephrolithiasis. The crude model was not adjusted, while Model 1 was adjusted for race, hypertension, and diabetes. Model 2 was adjusted for race, hypertension, diabetes status, and alcohol consumption. Model 3 was adjusted for age, gender, race, education level, marital status, family PIR, BMI, total cholesterol (TC), high-density lipoprotein cholesterol (HDL), hypertension, diabetes, alcohol consumption, smoking status, SAT, and TAT. Trend tests (p value for trend) were performed by entering VAT (quartile-categorical) as a continuous variable, with the first quartile of VAT serving as the reference group. Furthermore, an analysis of possible nonlinear relationships between VAT volume and the risk of nephrolithiasis was carried out using restricted cubic splines (RCSs).

MR analyses

Data sources and SNP selection for VAT and nephrolithiasis.

The primary genetic data were obtained from a recent GWAS on VAT involving 325,153 European males (n = 164,004) and females (n = 161,149). Summary data for the predicted VAT from the GWAS are accessible at https://www.ebi.ac.uk/gwas/search?query=GCST008744. SNPs that exhibited a significant association with VAT (p < 5 × 10^− 8, LD r2 < 0.001) were selected. F-statistics were computed to identify strong IVs (F > 10)¹⁴. To ascertain whether there were SNPs linked to confounders, the Phenoscanner database was examined for SNPs associated with exposure. The MR-PRESSO test was used to eliminate outliers¹⁵.

The GWAS summary data for nephrolithiasis were selected from a UK Biobank-based GWAS that included individuals of 388,508 controls and 6536 stone formers¹⁶.

Statistical analysis

To evaluate the causal relationship between VAT and nephrolithiasis through the combination of multiple SNPs, a two-sample Mendelian randomization analysis was conducted using three primary methods: the inverse variance weighted (IVW) method, weighted median, and MR‒Egger regression^14,17,18. To further validate the stability of the Mendelian randomization results, additional sensitivity analyses were performed. First, Cochran's Q statistic was utilized to quantify heterogeneity, followed by the MR‒Egger intercept test to evaluate the presence of horizontal pleiotropy¹⁵. Additionally, a leave-one-out analysis was conducted to verify the consistency of the findings by removing each SNP individually¹⁹.

All the statistical analyses were performed using R software (version 4.0.3), and the MR analyses were performed using the two-sample MR package (version 0.5.6). All p values were considered two-sided, and a p value < 0.05 indicated statistical significance.

Observational results between VAT and nephrolithiasis in the NHANES

Participant characteristics

The overall weighted incidence of nephrolithiasis was 9.1%. The characteristics of the study subjects stratified by nephrolithiasis are presented in Table 1. There were statistically significant differences in age, race, marital status, BMI, HDL cholesterol, diabetes status, hypertension status, alcohol consumption, smoking status, SAT, TAT, and VAT between the nephrolithiasis group and the control group (p < 0.05).

Table 1

Characteristics of the study subjects stratified by nephrolithiasis.
Characteristic	Overall, N = 8570 (100%)¹	Control, N = 7847 (91%)¹	Nephrolithiasis, N = 723 (9.1%)¹	p value²
Gender				0.7
Male	4,547 (53%)	4,174 (53%)	373 (52%)
Female	4,023 (47%)	3,673 (47%)	350 (48%)
Age(years)	40 (12)	39 (12)	43 (11)	< 0.001
Race				< 0.001
Mexican American	1,179 (9.2%)	1,081 (9.3%)	98 (8.0%)
Other Hispanic	819 (6.4%)	731 (6.4%)	88 (6.6%)
Non-Hispanic White	3,383 (66%)	3,020 (65%)	363 (73%)
Non-Hispanic Black	1,795 (10%)	1,696 (11%)	99 (6.2%)
Others	1,394 (8.3%)	1,319 (8.6%)	75 (6.1%)
Education level				0.2
Less than 9th grade	375 (2.7%)	347 (2.7%)	28 (2.3%)
9-11th grade	988 (8.6%)	892 (8.5%)	96 (9.5%)
High school graduate/GED	1,869 (21%)	1,712 (21%)	157 (23%)
Some college or AA degree	2,934 (34%)	2,638 (34%)	296 (37%)
College graduate or above	2,404 (33%)	2,258 (34%)	146 (28%)
Marital status				< 0.001
Married	4,113 (52%)	3,735 (51%)	378 (58%)
Widowed	121 (1.2%)	112 (1.2%)	9 (0.9%)
Divorced	846 (9.8%)	746 (9.4%)	100 (14%)
Separated	300 (2.5%)	268 (2.5%)	32 (2.6%)
Never married	2,190 (23%)	2,060 (24%)	130 (15%)
Living with partner	1,000 (11%)	926 (11%)	74 (8.9%)
family PIR				0.5
< 1.3	2,600 (21%)	2,366 (21%)	234 (21%)
1.3–3.5	3,127 (35%)	2,869 (34%)	258 (37%)
> 3.5	2,843 (45%)	2,612 (45%)	231 (42%)
BMI (kg/m2)				< 0.001
Normal or low weight	2,575 (30%)	2,422 (31%)	153 (21%)
Overweight	2,699 (32%)	2,483 (33%)	216 (31%)
Obese	3,296 (38%)	2,942 (37%)	354 (49%)
TC (mg/dL)	193 (41)	192 (40)	196 (51)	0.2
HDL (mg/dL)	53 (16)	53 (16)	50 (15)	< 0.001
Diabetes				< 0.001
NO	7,771 (92%)	7,176 (93%)	595 (83%)
Borderline	154 (1.7%)	129 (1.4%)	25 (4.0%)
YES	645 (6.1%)	542 (5.4%)	103 (13%)
Hypertension				< 0.001
NO	6,445 (76%)	5,990 (78%)	455 (63%)
YES	2,125 (24%)	1,857 (22%)	268 (37%)
Alcohol				< 0.001
NO	1,134 (12%)	990 (11%)	144 (18%)
YES	7,436 (88%)	6,857 (89%)	579 (82%)
Smoke				0.006
Never	4,758 (55%)	4,416 (56%)	342 (48%)
Former	1,676 (22%)	1,507 (22%)	169 (25%)
Current	2,136 (23%)	1,924 (22%)	212 (27%)
SAT (cm3)	1,775 (883)	1,755 (883)	1,965 (862)	< 0.001
TAT (cm3)	2,329 (1,089)	2,295 (1,083)	2,667 (1,089)	< 0.001
VAT (cm3)	555 (311)	540 (302)	702 (353)	< 0.001
¹n (unweighted) (%); Mean (SD)
²chi-squared test with Rao & Scott's second-order correction; Wilcoxon rank-sum test for complex survey samples family PIR, ratio of family income to poverty threshold; BMI, Body Mass Index; TC, Total Cholesterol; HDL, HDL-Cholesterol; VAT, Visceral adipose tissue; SAT, Subcutaneous adipose tissue; TAT, Total abdominal adipose tissue.

Multivariate regression analysis

As summarized in Table 2, individuals in the highest quartile (Quartile 4) of VAT exhibited a markedly elevated risk of developing nephrolithiasis compared to those in the lowest quartile (Quartile 1). This elevated risk was statistically significant in the crude model (OR [95% CI], 3.00 [1.78, 5.07]), as well as in Model 1 (OR [95% CI], 2.24 [1.28, 3.92]), Model 2 (OR [95% CI], 2.18 [1.24, 3.83]), and Model 3 (OR [95% CI], 1.95 [0.99, 3.82]). Furthermore, the p value for the trend analysis was less than 0.05 in all the models.

Table 2

Multivariate regression analysis between VAT and nephrolithiasis
Variable	Crude	Model1	Model2	Model3
Variable	OR (95% CI)	OR (95% CI)	OR (95% CI)	OR (95% CI)
VAT (cm³)
Quartile 1	reference	reference	reference	reference
Quartile 2	1.41(0.92, 2.17)	1.35(0.88, 2.09)	1.33(0.86, 2.05)	1.28(0.79, 2.08)
Quartile 3	1.54(0.93, 2.54)	1.31(0.78, 2.21)	1.3(0.77, 2.18)	1.19(0.66, 2.12)
Quartile 4	3.00(1.78, 5.07)	2.24(1.28, 3.92)	2.18(1.24, 3.83)	1.95(0.99, 3.82)
p for trend	< 0.001	0.003	0.005	0.029
The crude material was not adjusted. Model 1 was adjusted for race, hypertension, and diabetes, and Model 2 was adjusted for race, hypertension, diabetes, and alcohol. Model3 for age, gender, race, education level, marital status, family PIR, BMI, total cholesterol (TC), high-density lipoprotein cholesterol (HDL), hypertension, diabetes, alcohol, smoking, SAT, and TAT. VAT, Visceral adipose tissue.

Restricted cubic splines (RCSs) analysis

As Fig. 1 illustrates, the analysis conducted using regression calibration spline (RCSs) revealed a linear relationship between visceral adipose tissue (VAT) and nephrolithiasis, even after accounting for potential confounders (p-nonlinear = 0.443).

Two-sample MR analysis

In this study, we analyzed 225 statistically significant VAT-associated SNPs (with p < 5 × 10^− 8 and LD r² < 0.001), 27 of which were present in the nephrolithiasis dataset. After searching for additional VAT-associated SNPs in the PhenoScanner database, we identified two SNPs (rs11776713 and rs56094641) linked to treatment with bendroflumethiazide, a drug considered protective against nephrolithiasis²⁰. The F-statistics for the IVs of VAT exceeded the threshold of 10, indicating that these IVs were robust and likely to minimize estimation bias. We further refined our analysis using the MR-PRESSO test to remove outliers, resulting in the exclusion of two SNPs (rs10423928 and rs7165759) and the inclusion of 23 SNPs as IVs in our nephrolithiasis analysis.

As Fig. 2 illustrates, Cochran's Q test revealed the presence of heterogeneity (P < 0.05). Consequently, we employed a random-effects model using the inverse variance weighted (IVW) method. Our findings suggest a causal association between genetically elevated VAT and nephrolithiasis (OR [95% CI], 1.03 [1.02, 1.04]; P < 0.001). The results obtained from the weighted median model were consistent with those from IVW (OR [95% CI], 1.03 [1.02, 1.04]; P < 0.001). However, the MR‒Egger method indicated no causal effects of genetically predicted VAT on nephrolithiasis (OR [95% CI], 0.99 [0.96, 1.03]; P = 0.64). Furthermore, the MR‒Egger analysis did not suggest any directional pleiotropy for the IVs (P for intercept = 0.06). Finally, our leave-one-out sensitivity analysis demonstrated that no single SNP had a significant impact on the overall pooled results.

The results of our study indicate a positive linear relationship between visceral adipose tissue (VAT) and nephrolithiasis, suggesting that as VAT increases, the risk of developing nephrolithiasis also increases. To further investigate this potential causal relationship, we utilized a two-sample Mendelian randomization (MR) approach, which provided evidence supporting a causal role of genetically predicted VAT in nephrolithiasis risk. To the best of our knowledge, this represents the first study to explore the causal link between VAT and nephrolithiasis using large-scale observational data in conjunction with MR analyses.

The relationship between VAT and nephrolithiasis, while not fully understood, is gaining recognition. Our findings align with previous research identifying VAT as a risk factor for nephrolithiasis^11,12,21,22. However, one study reported conflicting results, suggesting a stronger association between subcutaneous fat and nephrolithiasis risk²³. Key differences in study design, including sample size, age group, and study type, may account for this discrepancy. To enhance reliability, we treated VAT volume as a continuous variable and employed restricted cubic splines (RCSs) to confirm that VAT volume was linearly related to nephrolithiasis. Subsequently, a two-sample Mendelian randomization approach was employed to explore the causal association between VAT and nephrolithiasis. Notably, our study revealed a positive causal link between VAT and nephrolithiasis.

The underlying mechanisms linking VAT to nephrolithiasis are incompletely understood but are likely multifaceted. VAT may contribute to nephrolithiasis development through several pathways, including the secretion of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), which can trigger chronic inflammation and kidney dysfunction⁸. Additionally, insulin resistance in VAT may lead to elevated blood glucose and insulin levels, affecting urine composition and crystal formation²⁴. VAT may also influence kidney handling of salt, as adipocytes can secrete aldosterone, a hormone that regulates sodium and water reabsorption ²⁵. Finally, VAT may disrupt calcium homeostasis, a known factor in nephrolithiasis formation ²⁶.

Our study has several strengths. First, the large-scale data provided robust statistical power to detect associations between VAT and nephrolithiasis. Second, exploring the potential linear relationship between these variables offers new insights into this complex association. Third, compared with traditional observational studies, the MR approach employs genetic variants as proxies for VAT, minimizing biases associated with reverse causation and confounding factors.

Despite these strengths, several limitations should be noted. Self-reported nephrolithiasis information in the NHANES dataset may have introduced recall or reporting biases. Additionally, the lack of stone composition data prevented stratified analyses by stone type. Our findings are also primarily applicable to European and American populations, limiting generalizability to other ethnic groups.

In conclusion, our findings point to a positive and linear association between VAT volume and nephrolithiasis risk. The Mendelian randomization (MR) approach has provided evidence supporting a causal role of genetically predicted VAT in nephrolithiasis risk. Future research should therefore prioritize the elucidation of the underlying mechanisms involved and the confirmation of these findings in diverse populations.

Author Contribution: The authors contributed to the conception and design of the study, data collection and analysis, interpretation of the findings, and writing and revision of the manuscript. The author read and approved the final manuscript.

Ethical Statement: The data used in this study were obtained from a previous study in which informed consent was obtained from all participants. No additional informed consent was required for the present study.

Conflicts of interest: The authors declare no conflicts of interest.

Data availability: The data presented in this article can be accessed in the main text and supplementary materials.

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No competing interests reported.

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Visceral adipose tissue and nephrolithiasis risk: Evidence from National Health and Nutrition Examination Survey and Mendelian randomization analysis

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Abstract

Figures

Introduction

Materials and Methods

Observational study

Data sources and participants

Collection and definition of variables

Statistical analysis

MR analyses

Statistical analysis

Results

Observational results between VAT and nephrolithiasis in the NHANES

Participant characteristics

Multivariate regression analysis

Restricted cubic splines (RCSs) analysis

Two-sample MR analysis

Discussion

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

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