U-shaped relationship between serum vitamin C concentration and prevalence of kidney stones:a cross-sectional study from NHANES

U-shaped relationship between serum vitamin C concentration and prevalence of kidney stones:a cross-sectional study from NHANES | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article U-shaped relationship between serum vitamin C concentration and prevalence of kidney stones:a cross-sectional study from NHANES Jiahang Liu, Jinyu Tian, Hongfei Li, Xudong Yang, ShengJie Yu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7978482/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The relationship between vitamin C levels and the risk of kidney stone formation remains controversial. This study aimed to investigate the association between serum vitamin C concentration and renal calculi occurrence. Methods A cross-sectional analysis was conducted using data from the 2017–2018 National Health and Nutrition Examination Survey, comprising 4932 participants. Serum vitamin C concentrations were measured by ultra performance liquid chromatography. The prevalence of kidney stones among participants was determined through self-reported questionnaires. Segmented regression analysis identified a serum vitamin C threshold value of 1.69 mg/dL, the significance of which was confirmed by a log-likelihood ratio test. Subsequently, three logistic regression models were constructed to examine the effects of excess (≥ 1.69 mg/dL) versus non-excess serum vitamin C on kidney stones. Stratified analyses were conducted to evaluate the applicability of these models across different populations. Results The prevalence of kidney stones among participants was 10.22%. A U-shaped relationship was observed between serum vitamin C concentration and kidney stone prevalence, with a threshold identified at 1.69 mg/dL. Below this threshold, each unit increase in serum vitamin C concentration decreased kidney stone incidence by 29%. Conversely, above this threshold, kidney stone prevalence was positively correlated with serum vitamin C concentrations. Conclusions This study identified a nonlinear relationship between serum vitamin C concentration and kidney stone risk, indicating that both excessively high and low serum vitamin C levels are associated with increased risk. These findings underscore the importance of maintaining appropriate serum vitamin C levels for kidney stone prevention; however, further clinical studies are required to validate our conclusions. Kidney stones Vitamin C Kidney disease NHANES Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Kidney stones represent a prevalent urological disorder, with their incidence in the United States rising markedly from 1 in 20 in 1994 to 1 in 11[ 1 ]. Globally, prevalence rates differ across age, sex, and ethnicity, yet a general upward trend is observe[ 1 – 4 ]. As this prevalence increases, the socio-economic burden of kidney stones intensifies, accompanied by a substantial rise in healthcare resource utilization[ 5 ]. Vitamin C, or ascorbic acid, is a water-soluble vitamin that must be obtained through diet as it cannot be synthesized endogenously[ 6 ]. It is integral to human metabolism, facilitating non-heme iron absorption, participating in collagen synthesis, enhancing immune function, and exhibiting antioxidant properties[ 7 ]. Thus, maintaining sufficient vitamin C intake is vital for health and disease prevention. Recent studies suggest a protective role of vitamin C against kidney stone formation (8–9). To further investigate this relationship, we conducted a literature review. Our analysis revealed inconsistencies in clinical study outcomes regarding vitamin C and kidney stones, with some results being contradictory[ 8 – 14 ]. Consequently, we examined the association between serum vitamin C levels and kidney stone risk using data from the 2017–2018 NHANES . Methods Objects and methods of study The NCHS conducts the extensive NHANES survey to assess the health and nutritional status of the American people. Approved by the NCHS Ethics Review Board, all participants provided informed consent. A wide range of demographic information, physical examinations, lab tests, health-related questions, and prescription medication records are all included in the survey. The official Centers for Disease Control and Prevention website ( https://www.cdc.gov/nchs/nhanes/ ) has access to all of the data. We utilized data from the 2017–2018 NHANES cycle and employed R software 4.1 along with EmpowerStats 4.0 for visualization and analysis. Our study initially included 9,254 participants; after excluding those with missing kidney stone data (n = 3,685) and missing serum vitamin C data (n = 637), the final analysis comprised 4,932 participants. ( Fig. 1) Measurement of Serum vitamin C concentrations In NHANES, 2017–2018 Serum vitamin C concentrations is tested using UPLC with the use of electrochemical at 450 mV, after acidification and stabilization with metaphosphoric acid, injection onto a C-18 column, and comparison with an internal standard for quantitation. Outcome Definitions of Kidney stone Outcome Definitions of Kidney stone Definition of kidney stone outcome: We used a questionnaire to determine the renal health status of the participants. “Ever had kidney stones?” was used to assess the patient's kidney stone status, and if the participant answered ‘yes’ he was considered to have kidney stones. The occurrence of kidney stones was designed as an outcome variable. Previous studies have validated the reliability of self-reported history of kidney stones in the form of questionnaires. For example, Curhan et al. randomly reviewed the medical records of 60 participants who self-reported a history of kidney stones, resulting in a confirmed diagnosis in 97% of cases; the remaining 3% of cases were diagnosed with bladder stones. This supports the validity of self-reported history of kidney stones in large-scale epidemiologic surveys such as NHANES.(15) This supports the validity of self-reported history of kidney stones in large-scale epidemiologic surveys such as NHANES. Covariables Multivariate models were used to control for potential confounders in the association between kidney stones and serum vitamin C levels. The covariates analyzed included sex, years of age, ethnicity, education level, PIR , BMI , smoking status, hypertension, diabetes, and dietary vitamin C intake. Detailed measurement procedures for these variables can be accessed via the CDC website ( www.cdc.gov/nchs/nhanes/ ). Statistics and analysis All statistical analyses adhered to the guidelines of the CDC. Chi-square testing were applied for categorical data, while linear regression modeling was performed for continuous variables to analyze differences between persons with and without kidney stones.For continuous variables, the data were shown as means with standard deviations, and for categorical variables, as percentages. Segmented regression was subsequently conducted to identify the critical value of serum vitamin C concentration. A log-likelihood ratio test determined the existence of a threshold between the unsegmented and segmented regression models, with thresholds serving as critical values for categorization. A serum vitamin C threshold of 1.69 mg/dL was determined. Three logistic regression models were constructed to estimate ORs and 95% CIs for the relationship between serum vitamin C levels, classified as excessive (≥ 1.69 mg/dL) or non-excessive, and kidney stone incidence: a crude model (unadjusted), Model 1 adjusted for sex, years of age, ethnicity, education level, and PIR, and Model 2 further adjusted for BMI, smoking status, diabetes, hypertension, and dietary vitamin C intake. Analyses were stratified by sex, age (in tertiles), race/ethnicity, BMI (< 25.00 vs. ≥ 25.00),diabetes as well as hypertension history. Statistical significance was defined at a two-tailed P-value of less than 0.05 for all analyses, which were performed using EmpowerStats 4.0 and R version 4.1 software. Results Baseline attributes of research subjects 48.20% of the 4,932 individuals in the study were male, and their mean age was 51.60 ± 17.64 years. Kidney stone and non-kidney stone groups may be distinguished based on the overall kidney stone prevalence of 10.22%. When participant characteristics were evaluated, it was shown that the kidney stone group had a significantly lower serum vitamin C concentration (0.84 ± 0.55 mg/dL) than the non-stone group (0.90 ± 0.49 mg/dL) (P = 0.008). Furthermore, there was a significant correlation (P < 0.001) between the kidney stone-afflicted individuals' age, gender, non-Hispanic white race, obesity, diabetes, and hypertension. There were no statistically significant differences in vitamin C intake, household income, or education level (P > 0.05). (Table 1). Analysis of nonlinear relationships This study employed generalized additive modeling and smoothed curve fitting to investigate the nonlinear relationship between serum vitamin C concentration and kidney stone prevalence. A U-shaped association was identified (Fig. 2 ). A log-likelihood ratio test confirmed the presence of a threshold between the unsegmented and segmented regression models. The analysis demonstrated a significant nonlinear relationship (P < 0.05 for all log-likelihood ratios) (Table 2), pinpointing the inflection point at 1.69 mg/dL. Below this threshold, the incidence of kidney stones increased by 31% for every unit drop in serum vitamin C content (OR = 0.69, 95% CI = 0.52–0.91). However, no convincing association was found at 1.69 mg/dL (OR = 1.45, 95% CI = 0.83–2.52). Relationship between serum vitamin C concentration and prevalence of kidney stones The study included 4,932 participants, of whom 504 had kidney stones. Three logistic regression models were developed to investigate the independent effects of serum vitamin C concentration on kidney stone prevalence (Table 3). After adjusting for age, gender, ethnicity, education level, PIR, BMI, smoking status, history of hypertension, history of diabetes, and dietary vitamin C intake in Model 2, we found that serum vitamin C concentration was negatively associated with kidney stone prevalence when below 1.69 mg/dL. The OR was 0.71 (95% CI: 0.52–0.91), indicating a 29% reduction in likelihood of developing kidney stones for each unit increase in serum vitamin C concentration. Conversely, when serum vitamin C concentration exceeded 1.69 mg/dL, the prevalence of kidney stones was positively associated (OR = 2.14, 95% CI = 1.01–4.54). Subgroup analyses We conducted stratified analyses by age, gender, ethnicity, BMI, and past medical history of diabetes mellitus and hypertension to further investigate the relationship between ascorbic acid concentrations and kidney stone prevalence (Fig. 3 , 4 ). The effect of non-excessive (serum vitamin C < 1.69 mg/dL) versus excessive serum vitamin C (≥ 1.69 mg/dL) on kidney stone prevalence was consistent across subgroups stratified by age, ethnicity, BMI, history of hypertension, and diabetes, with no significant interaction between serum vitamin C concentration and these stratification variables. Notably, a stronger negative association was observed in women with serum vitamin C levels below 1.69 mg/dL (OR = 0.51, 95% CI = 0.33–0.79). Discussion This cross-sectional study included 4,932 participants and aimed to investigate the relationship between ascorbic acid concentration and kidney stone prevalence. A U-shaped relationship was observed: serum vitamin C concentrations below 1.69 mg/dL were negatively correlated with kidney stone prevalence, while concentrations of 1.69 mg/dL or higher showed a positive correlation. These findings may serve as an important reference for clinical practice and dietary recommendations to help reduce the prevalence of kidney stones. Our study employed serum vitamin C concentration as the independent variable and kidney stone prevalence as the dependent variable, revealing a nonlinear association between the two. In contrast to previous clinical studies, which often used vitamin C intake as the independent variable, we focused on serum concentration. For instance, Liu Kot K et al. reported that a daily intake of 60–110 mg of vitamin C could reduce stone formation risk[ 11 ], suggesting a beneficial effect of moderate ascorbic acid levels on kidney stone risk. Conversely, Massey LK observed an increased risk of oxaluria and kidney stones with excessive vitamin C intake[ 12 ]. The intricate and nonlinear link between vitamin C intake and the development of kidney stones is shown by these findings. Additionally, Zeng et al. found a similar trend where kidney stone prevalence decreased and then increased with rising vitamin C intake, aligning with our findings. However, Curhan GC et al. did not find a significant association between vitamin C intake and kidney stone risk in their long-term study of 85,557 women[ 8 ], differing from our results. This discrepancy may arise from differences in study populations and individual variations in vitamin C metabolism. Serum vitamin C concentration, primarily influenced by dietary intake[ 15 ], reflects the actual vitamin C levels in the body and may better capture its influence on kidney stone formation mechanisms. This perspective enhances the understanding of the relationship between ascorbic acid and Renal calculi, emphasizing the clinical importance of serum vitamin C concentration. The mechanism of renal stone formation remains incompletely understood. However, it is known to be closely associated with factors such as elevated urinary oxalate, high calcium, low urinary citrate, and oxidative stress in the kidneys[ 16 ]. These conditions can induce renal epithelial cells to adopt an osteoclast-like phenotype, promoting calcium phosphate crystal deposition, Randall plaque formation, and ultimately renal stone development. The influence of increasing serum vitamin C concentrations on kidney stone formation involves several complex mechanisms. Initially, vitamin C serves as an antioxidant, potentially mitigating renal tissue damage from oxidative stress, which originates from mitochondrial dysfunction and excessive ROS production that fosters crystal aggregation, growth, and adhesion[ 17 ]. By neutralizing excess ROS through redox reactions[ 18 ], vitamin C reduces oxidative stress in kidney cells, temporarily lowering the risk of stone formation. However, higher serum vitamin C levels can lead to increased urinary oxalate and urine acidification, raising the risk of stone formation, as vitamin C is primarily excreted by the kidneys, with approximately 44% metabolized as oxalate[ 19 ]. Vitamin C reabsorption relies on the SVCT1 transporter protein, which effectively removes excess vitamin C to maintain stable plasma levels[ 19 ]. Consequently, elevated serum vitamin C results in increased urinary oxalate levels, promoting the crystallization or aggregation of crystalline constituents[ 20 ]. Moreover, vitamin C's acidic nature can further acidify urine, enhancing oxalate precipitation and crystallization. Thus, maintaining optimal serum vitamin C levels may reduce kidney stone risk. It is crucial to carefully manage vitamin C intake, particularly in individuals with or at risk for kidney stones. Vitamin C plays a dual role: its antioxidant properties must be balanced against the risk of oxalate formation to minimize adverse effects. Previous studies have identified gender, ethnicity, obesity, and diabetes as influential factors in the prevalence of kidney stones[ 1 ].As a result, we performed a stratified analysis according to gender, age, ethnicity, obesity, diabetes, and hypertension. Consistent with earlier findings, our analysis showed that men have a higher likelihood of developing kidney stones[ 1 , 2 ]. Interestingly, we observed that non-excess serum vitamin C (< 1.69 mg/dL) offered more protection against kidney stones in women. This may be attributed to estrogen, which enhances antioxidant capacity through various mechanisms, providing more effective protection against oxidative stress-related kidney stone formation[ 21 ]. Consequently, women may experience a more pronounced protective effect than men. However, in the case of excess serum vitamin C (≥ 1.69 mg/dL), no significant interaction between gender and kidney stone prevalence was detected. Furthermore, across subgroups stratified by age, ethnicity, obesity, past medical history of diabetes mellitus and hypertension serum vitamin C concentrations showed no significant interactions with these stratification variables. Our study has several strengths. First, unlike previous clinical studies that typically used vitamin C intake as the independent variable to explore its relationship with kidney stones, we used serum vitamin C concentration. This innovative approach provides a new perspective on the relationship between vitamin C and renal calculi. Second, This research utilized nationally representative data from NHANES, making the findings more generalizable to diverse populations. Additionally, we adjusted for covariates to minimize confounding factors, thereby enhancing the reliability of our results and their applicability to broader demographics. Finally, stratified analyses allowed us to identify differences among subgroups, considering the characteristics of various populations and further enhancing the generalizability of our conclusions. However, this study has limitations. Despite the strengths of this study, including the use of a nationally representative large sample and multivariable adjustments to enhance the robustness of the results, several limitations remain. First, as a cross-sectional study, both the exposure (serum vitamin C concentration) and the outcome (kidney stone prevalence) were measured simultaneously, preventing the determination of a temporal sequence and thereby limiting causal inference. Second, although adjustments were made for multiple covariates, potential unmeasured confounders—such as medication use, genetic susceptibility, and lifestyle factors—may still influence the results, and their effects cannot be entirely ruled out. Therefore, the findings of this study can only suggest a statistical association between serum vitamin C levels and kidney stone prevalence rather than a causal relationship. Prospective cohort studies or randomized controlled trials are needed in the future to verify the causal basis of this observed U-shaped association. Additionally, some of the data used in this study were derived from questionnaires or interviews, which may introduce a degree of recall bias and should be interpreted with caution. Conclusions In conclusion, this study reveals a significant nonlinear (U-shaped) association between serum vitamin C concentration and the prevalence of kidney stones, with a threshold at 1.69 mg/dL. Although causal relationships cannot be established due to the cross-sectional design, the findings offer new insights for clinical nutrition management. Particularly for high-risk populations such as individuals with obesity, diabetes, or a history of kidney stones, careful control of vitamin C intake may be of reference value. Public health education should further emphasize the principle of “moderate supplementation and avoidance of extremes,” encouraging the maintenance of appropriate serum vitamin C levels through a balanced diet. Future prospective studies are warranted to validate these findings and to explore whether serum vitamin C concentration can serve as a potential biomarker for identifying individuals at high risk of kidney stone formation, thereby supporting individualized nutritional intervention strategies. Declarations Ethics approval and consent to participate: The protocols of NHANES were approved by the institutional review board of the National Center for Health Statistics, CDC ( https://www.cdc.gov/nchs/nhanes/irba98.htm ). NHANES has obtained written informed. Consent for publication: Not applicable. Clinical trial number not applicable. Competing interests: The authors declare that they have no competing interests. Authors' information Jia-hang Liu, Sheng-Jie Yu, Urology Department, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China Funding: Not applicable. Author Contribution J.L. and S.Y. conceived the study and designed the methodology. J.L., J.T., and H.L. were responsible for data curation and formal analysis. J.L. and X.Y. performed the statistical analysis. J.L. wrote the original draft of the manuscript. All authors (J.T., H.L., X.Y., S.Y.) critically reviewed, edited, and approved the final version of the manuscript. S.Y. supervised the project and had primary responsibility for the final content. Data Availability The datasets generated and analyzed in the current study are available at NHANES website:(https://www.cdc.gov/nchs/nhanes/) References Scales CD Jr, Smith AC, Hanley JM, Saigal CS, Project UDiA (2012). Prevalence of kidney stones in the United States. European urology.62(1):160-5. https://doi.org/10.1016/j.eururo.2012.03.052 Chewcharat A, Curhan G (2021) Trends in the prevalence of kidney stones in the United States from 2007 to 2016. Urolithiasis.49(1):27–39. https://doi.org/10.1007/s00240-020-01210-w Romero V, Akpinar H, Assimos DG (2010) Kidney stones: a global picture of prevalence, incidence, and associated risk factors. Rev Urol 12(2–3):e86–96. https://doi.org/10.3909/riu0509 Wang W, Fan J, Huang G, Li J, Zhu X, Tian Y et al (2017) Prevalence of kidney stones in mainland China: a systematic review. 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Orthop J Sports Med 6(10):2325967118804544. https://doi.org/10.1177/2325967118804544 Doseděl M, Jirkovský E, Macáková K, Krčmová LK, Javorská L, Pourová J et al (2021) Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination. Nutrients.13(2). https://doi.org/10.3390/nu13020615 Wang Z, Zhang Y, Zhang J, Deng Q, Liang H (2021) Recent advances on the mechanisms of kidney stone formation (Review). Int J Mol Med 48(2). https://doi.org/10.3892/ijmm.2021.4982 Michos C, Kiortsis DN, Evangelou A, Karkabounas S (2006) Antioxidant protection during the menstrual cycle: the effects of estradiol on ascorbic-dehydroascorbic acid plasma levels and total antioxidant plasma status in eumenorrhoic women during the menstrual cycle. Acta Obstet Gynecol Scand 85(8):960–965. https://doi.org/10.1080/00016340500432812 Footnotes NHANES National Health and Nutrition Examination Survey NCHS National Center for Health Statistics UPLC Ultra Performance Liquid Chromatography PIR poverty-to-income ratio BMI body mass index OR the odds ratio 95% CI confidence interval ROS Reactive Oxygen Species Tables Tables are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Onlinefloatimage2.png Onlinefloatimage4.png Onlinefloatimage5.png Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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1","display":"","copyAsset":false,"role":"figure","size":128004,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7978482/v1/d4967c420a0d45bbd36528e8.jpg"},{"id":95877280,"identity":"c1342402-d2dd-4586-a1d7-2bb410a96c1a","added_by":"auto","created_at":"2025-11-14 01:41:47","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":79039,"visible":true,"origin":"","legend":"\u003cp\u003eU-shaped relationship between serum vitamin C and kidney stones\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7978482/v1/c000e8c45ced7bdba712b2e9.jpg"},{"id":95877285,"identity":"e426c8bc-b9cd-4518-87d0-f0598e563834","added_by":"auto","created_at":"2025-11-14 01:41:48","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":157060,"visible":true,"origin":"","legend":"\u003cp\u003eStratified analysis forest plot (serum vitamin C \u0026lt; 1.69 mg/dL)\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7978482/v1/fadd73ed4482df54b2a8735f.jpg"},{"id":96242119,"identity":"0141138e-7bf7-482e-8bfc-91cd514e64ed","added_by":"auto","created_at":"2025-11-19 07:12:07","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":139689,"visible":true,"origin":"","legend":"\u003cp\u003eStratified analysis forest plot (serum vitamin C ≥ 1.69 mg/dL)\u003c/p\u003e","description":"","filename":"Picture4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7978482/v1/e91a9547a237b87fecbfe0f8.jpg"},{"id":96363310,"identity":"4e2e88c5-515a-40f7-bab7-a163fa7f7997","added_by":"auto","created_at":"2025-11-20 10:06:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1122492,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7978482/v1/2c341b52-78b9-427d-8c42-b51efb881a36.pdf"},{"id":96241153,"identity":"28fb53e5-f799-4104-94e8-ec78c3466cd7","added_by":"auto","created_at":"2025-11-19 07:10:20","extension":"png","order_by":11,"title":"","display":"","copyAsset":false,"role":"supplement","size":24938,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7978482/v1/92e0cd4d53d3f05e7e7263df.png"},{"id":96242966,"identity":"99469638-f307-4937-b2c8-7ad000ae9177","added_by":"auto","created_at":"2025-11-19 07:15:03","extension":"png","order_by":13,"title":"","display":"","copyAsset":false,"role":"supplement","size":8089,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7978482/v1/371ac43110d2ddc3145851ec.png"},{"id":95877298,"identity":"47887bfb-b05f-492b-97f6-0e6d5b311a46","added_by":"auto","created_at":"2025-11-14 01:41:48","extension":"png","order_by":14,"title":"","display":"","copyAsset":false,"role":"supplement","size":11064,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7978482/v1/62ba5d7e92f6941f34188bbc.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"U-shaped relationship between serum vitamin C concentration and prevalence of kidney stones:a cross-sectional study from NHANES","fulltext":[{"header":"Introduction","content":"\u003cp\u003eKidney stones represent a prevalent urological disorder, with their incidence in the United States rising markedly from 1 in 20 in 1994 to 1 in 11[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Globally, prevalence rates differ across age, sex, and ethnicity, yet a general upward trend is observe[\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. As this prevalence increases, the socio-economic burden of kidney stones intensifies, accompanied by a substantial rise in healthcare resource utilization[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eVitamin C, or ascorbic acid, is a water-soluble vitamin that must be obtained through diet as it cannot be synthesized endogenously[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. It is integral to human metabolism, facilitating non-heme iron absorption, participating in collagen synthesis, enhancing immune function, and exhibiting antioxidant properties[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Thus, maintaining sufficient vitamin C intake is vital for health and disease prevention.\u003c/p\u003e\u003cp\u003eRecent studies suggest a protective role of vitamin C against kidney stone formation (8\u0026ndash;9). To further investigate this relationship, we conducted a literature review. Our analysis revealed inconsistencies in clinical study outcomes regarding vitamin C and kidney stones, with some results being contradictory[\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12 CR13\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Consequently, we examined the association between serum vitamin C levels and kidney stone risk using data from the 2017\u0026ndash;2018 NHANES\u003ca class=\"FNLink\" href=\"#Fn1\" id=\"#FNLinkFn1\"\u003e\u003c/a\u003e.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eObjects and methods of study\u003c/h2\u003e\u003cp\u003eThe NCHS\u003ca class=\"FNLink\" href=\"#Fn2\" id=\"#FNLinkFn2\"\u003e\u003c/a\u003e conducts the extensive NHANES survey to assess the health and nutritional status of the American people. Approved by the NCHS Ethics Review Board, all participants provided informed consent. A wide range of demographic information, physical examinations, lab tests, health-related questions, and prescription medication records are all included in the survey. The official Centers for Disease Control and Prevention website (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.cdc.gov/nchs/nhanes/\u003c/span\u003e\u003cspan address=\"https://www.cdc.gov/nchs/nhanes/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) has access to all of the data. We utilized data from the 2017\u0026ndash;2018 NHANES cycle and employed R software 4.1 along with EmpowerStats 4.0 for visualization and analysis. Our study initially included 9,254 participants; after excluding those with missing kidney stone data (n\u0026thinsp;=\u0026thinsp;3,685) and missing serum vitamin C data (n\u0026thinsp;=\u0026thinsp;637), the final analysis comprised 4,932 participants. ( Fig.\u0026nbsp;1)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eMeasurement of Serum vitamin C concentrations\u003c/h3\u003e\n\u003cp\u003eIn NHANES, 2017\u0026ndash;2018 Serum vitamin C concentrations is tested using UPLC\u003ca class=\"FNLink\" href=\"#Fn3\" id=\"#FNLinkFn3\"\u003e\u003c/a\u003e with the use of electrochemical at 450 mV, after acidification and stabilization with metaphosphoric acid, injection onto a C-18 column, and comparison with an internal standard for quantitation.\u003c/p\u003e\n\u003ch3\u003eOutcome Definitions of Kidney stone\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003eOutcome Definitions of Kidney stone\u003c/div\u003e\u003cp\u003eDefinition of kidney stone outcome: We used a questionnaire to determine the renal health status of the participants. \u0026ldquo;Ever had kidney stones?\u0026rdquo; was used to assess the patient's kidney stone status, and if the participant answered \u0026lsquo;yes\u0026rsquo; he was considered to have kidney stones. The occurrence of kidney stones was designed as an outcome variable. Previous studies have validated the reliability of self-reported history of kidney stones in the form of questionnaires. For example, Curhan et al. randomly reviewed the medical records of 60 participants who self-reported a history of kidney stones, resulting in a confirmed diagnosis in 97% of cases; the remaining 3% of cases were diagnosed with bladder stones. This supports the validity of self-reported history of kidney stones in large-scale epidemiologic surveys such as NHANES.(15) This supports the validity of self-reported history of kidney stones in large-scale epidemiologic surveys such as NHANES.\u003c/p\u003e\n\u003ch3\u003eCovariables\u003c/h3\u003e\n\u003cp\u003eMultivariate models were used to control for potential confounders in the association between kidney stones and serum vitamin C levels. The covariates analyzed included sex, years of age, ethnicity, education level, PIR\u003ca class=\"FNLink\" href=\"#Fn4\" id=\"#FNLinkFn4\"\u003e\u003c/a\u003e, BMI\u003ca class=\"FNLink\" href=\"#Fn5\" id=\"#FNLinkFn5\"\u003e\u003c/a\u003e, smoking status, hypertension, diabetes, and dietary vitamin C intake. Detailed measurement procedures for these variables can be accessed via the CDC website (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"https://www.cdc.gov/nchs/nhanes/\" target=\"_blank\"\u003ewww.cdc.gov/nchs/nhanes/\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.cdc.gov/nchs/nhanes/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003eStatistics and analysis\u003c/h3\u003e\n\u003cp\u003e All statistical analyses adhered to the guidelines of the CDC. Chi-square testing were applied for categorical data, while linear regression modeling was performed for continuous variables to analyze differences between persons with and without kidney stones.For continuous variables, the data were shown as means with standard deviations, and for categorical variables, as percentages.\u003c/p\u003e\u003cp\u003eSegmented regression was subsequently conducted to identify the critical value of serum vitamin C concentration. A log-likelihood ratio test determined the existence of a threshold between the unsegmented and segmented regression models, with thresholds serving as critical values for categorization. A serum vitamin C threshold of 1.69 mg/dL was determined.\u003c/p\u003e\u003cp\u003eThree logistic regression models were constructed to estimate ORs\u003ca class=\"FNLink\" href=\"#Fn6\" id=\"#FNLinkFn6\"\u003e\u003c/a\u003e and 95% CIs\u003ca class=\"FNLink\" href=\"#Fn7\" id=\"#FNLinkFn7\"\u003e\u003c/a\u003e for the relationship between serum vitamin C levels, classified as excessive (\u0026ge;\u0026thinsp;1.69 mg/dL) or non-excessive, and kidney stone incidence: a crude model (unadjusted), Model 1 adjusted for sex, years of age, ethnicity, education level, and PIR, and Model 2 further adjusted for BMI, smoking status, diabetes, hypertension, and dietary vitamin C intake.\u003c/p\u003e\u003cp\u003eAnalyses were stratified by sex, age (in tertiles), race/ethnicity, BMI (\u0026lt;\u0026thinsp;25.00 vs. \u0026ge; 25.00),diabetes as well as hypertension history.\u003c/p\u003e\u003cp\u003eStatistical significance was defined at a two-tailed P-value of less than 0.05 for all analyses, which were performed using EmpowerStats 4.0 and R version 4.1 software.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eBaseline attributes of research subjects\u003c/h2\u003e\u003cp\u003e48.20% of the 4,932 individuals in the study were male, and their mean age was 51.60\u0026thinsp;\u0026plusmn;\u0026thinsp;17.64 years. Kidney stone and non-kidney stone groups may be distinguished based on the overall kidney stone prevalence of 10.22%. When participant characteristics were evaluated, it was shown that the kidney stone group had a significantly lower serum vitamin C concentration (0.84\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55 mg/dL) than the non-stone group (0.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49 mg/dL) (P\u0026thinsp;=\u0026thinsp;0.008). Furthermore, there was a significant correlation (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) between the kidney stone-afflicted individuals' age, gender, non-Hispanic white race, obesity, diabetes, and hypertension. There were no statistically significant differences in vitamin C intake, household income, or education level (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). (Table\u0026nbsp;1).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eAnalysis of nonlinear relationships\u003c/h3\u003e\n\u003cp\u003eThis study employed generalized additive modeling and smoothed curve fitting to investigate the nonlinear relationship between serum vitamin C concentration and kidney stone prevalence. A U-shaped association was identified (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e). A log-likelihood ratio test confirmed the presence of a threshold between the unsegmented and segmented regression models. The analysis demonstrated a significant nonlinear relationship (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 for all log-likelihood ratios) (Table\u0026nbsp;2), pinpointing the inflection point at 1.69 mg/dL. Below this threshold, the incidence of kidney stones increased by 31% for every unit drop in serum vitamin C content (OR\u0026thinsp;=\u0026thinsp;0.69, 95% CI\u0026thinsp;=\u0026thinsp;0.52\u0026ndash;0.91). However, no convincing association was found at 1.69 mg/dL (OR\u0026thinsp;=\u0026thinsp;1.45, 95% CI\u0026thinsp;=\u0026thinsp;0.83\u0026ndash;2.52).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eRelationship between serum vitamin C concentration and prevalence of kidney stones\u003c/h2\u003e\u003cp\u003eThe study included 4,932 participants, of whom 504 had kidney stones. Three logistic regression models were developed to investigate the independent effects of serum vitamin C concentration on kidney stone prevalence (Table\u0026nbsp;3). After adjusting for age, gender, ethnicity, education level, PIR, BMI, smoking status, history of hypertension, history of diabetes, and dietary vitamin C intake in Model 2, we found that serum vitamin C concentration was negatively associated with kidney stone prevalence when below 1.69 mg/dL. The OR was 0.71 (95% CI: 0.52\u0026ndash;0.91), indicating a 29% reduction in likelihood of developing kidney stones for each unit increase in serum vitamin C concentration. Conversely, when serum vitamin C concentration exceeded 1.69 mg/dL, the prevalence of kidney stones was positively associated (OR\u0026thinsp;=\u0026thinsp;2.14, 95% CI\u0026thinsp;=\u0026thinsp;1.01\u0026ndash;4.54).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eSubgroup analyses\u003c/h2\u003e\u003cp\u003eWe conducted stratified analyses by age, gender, ethnicity, BMI, and past medical history of diabetes mellitus and hypertension to further investigate the relationship between ascorbic acid concentrations and kidney stone prevalence (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e, \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The effect of non-excessive (serum vitamin C\u0026thinsp;\u0026lt;\u0026thinsp;1.69 mg/dL) versus excessive serum vitamin C (\u0026ge;\u0026thinsp;1.69 mg/dL) on kidney stone prevalence was consistent across subgroups stratified by age, ethnicity, BMI, history of hypertension, and diabetes, with no significant interaction between serum vitamin C concentration and these stratification variables. Notably, a stronger negative association was observed in women with serum vitamin C levels below 1.69 mg/dL (OR\u0026thinsp;=\u0026thinsp;0.51, 95% CI\u0026thinsp;=\u0026thinsp;0.33\u0026ndash;0.79).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis cross-sectional study included 4,932 participants and aimed to investigate the relationship between ascorbic acid concentration and kidney stone prevalence. A U-shaped relationship was observed: serum vitamin C concentrations below 1.69 mg/dL were negatively correlated with kidney stone prevalence, while concentrations of 1.69 mg/dL or higher showed a positive correlation. These findings may serve as an important reference for clinical practice and dietary recommendations to help reduce the prevalence of kidney stones.\u003c/p\u003e\u003cp\u003eOur study employed serum vitamin C concentration as the independent variable and kidney stone prevalence as the dependent variable, revealing a nonlinear association between the two. In contrast to previous clinical studies, which often used vitamin C intake as the independent variable, we focused on serum concentration. For instance, Liu Kot K et al. reported that a daily intake of 60\u0026ndash;110 mg of vitamin C could reduce stone formation risk[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], suggesting a beneficial effect of moderate ascorbic acid levels on kidney stone risk. Conversely, Massey LK observed an increased risk of oxaluria and kidney stones with excessive vitamin C intake[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The intricate and nonlinear link between vitamin C intake and the development of kidney stones is shown by these findings. Additionally, Zeng et al. found a similar trend where kidney stone prevalence decreased and then increased with rising vitamin C intake, aligning with our findings. However, Curhan GC et al. did not find a significant association between vitamin C intake and kidney stone risk in their long-term study of 85,557 women[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], differing from our results. This discrepancy may arise from differences in study populations and individual variations in vitamin C metabolism. Serum vitamin C concentration, primarily influenced by dietary intake[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], reflects the actual vitamin C levels in the body and may better capture its influence on kidney stone formation mechanisms. This perspective enhances the understanding of the relationship between ascorbic acid and Renal calculi, emphasizing the clinical importance of serum vitamin C concentration.\u003c/p\u003e\u003cp\u003eThe mechanism of renal stone formation remains incompletely understood. However, it is known to be closely associated with factors such as elevated urinary oxalate, high calcium, low urinary citrate, and oxidative stress in the kidneys[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. These conditions can induce renal epithelial cells to adopt an osteoclast-like phenotype, promoting calcium phosphate crystal deposition, Randall plaque formation, and ultimately renal stone development. The influence of increasing serum vitamin C concentrations on kidney stone formation involves several complex mechanisms. Initially, vitamin C serves as an antioxidant, potentially mitigating renal tissue damage from oxidative stress, which originates from mitochondrial dysfunction and excessive ROS\u003ca class=\"FNLink\" href=\"#Fn8\" id=\"#FNLinkFn8\"\u003e\u003c/a\u003e production that fosters crystal aggregation, growth, and adhesion[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. By neutralizing excess ROS through redox reactions[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], vitamin C reduces oxidative stress in kidney cells, temporarily lowering the risk of stone formation. However, higher serum vitamin C levels can lead to increased urinary oxalate and urine acidification, raising the risk of stone formation, as vitamin C is primarily excreted by the kidneys, with approximately 44% metabolized as oxalate[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Vitamin C reabsorption relies on the SVCT1 transporter protein, which effectively removes excess vitamin C to maintain stable plasma levels[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Consequently, elevated serum vitamin C results in increased urinary oxalate levels, promoting the crystallization or aggregation of crystalline constituents[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Moreover, vitamin C's acidic nature can further acidify urine, enhancing oxalate precipitation and crystallization. Thus, maintaining optimal serum vitamin C levels may reduce kidney stone risk. It is crucial to carefully manage vitamin C intake, particularly in individuals with or at risk for kidney stones. Vitamin C plays a dual role: its antioxidant properties must be balanced against the risk of oxalate formation to minimize adverse effects.\u003c/p\u003e\u003cp\u003ePrevious studies have identified gender, ethnicity, obesity, and diabetes as influential factors in the prevalence of kidney stones[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].As a result, we performed a stratified analysis according to gender, age, ethnicity, obesity, diabetes, and hypertension. Consistent with earlier findings, our analysis showed that men have a higher likelihood of developing kidney stones[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Interestingly, we observed that non-excess serum vitamin C (\u0026lt;\u0026thinsp;1.69 mg/dL) offered more protection against kidney stones in women. This may be attributed to estrogen, which enhances antioxidant capacity through various mechanisms, providing more effective protection against oxidative stress-related kidney stone formation[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Consequently, women may experience a more pronounced protective effect than men. However, in the case of excess serum vitamin C (\u0026ge;\u0026thinsp;1.69 mg/dL), no significant interaction between gender and kidney stone prevalence was detected. Furthermore, across subgroups stratified by age, ethnicity, obesity, past medical history of diabetes mellitus and hypertension serum vitamin C concentrations showed no significant interactions with these stratification variables.\u003c/p\u003e\u003cp\u003eOur study has several strengths. First, unlike previous clinical studies that typically used vitamin C intake as the independent variable to explore its relationship with kidney stones, we used serum vitamin C concentration. This innovative approach provides a new perspective on the relationship between vitamin C and renal calculi. Second, This research utilized nationally representative data from NHANES, making the findings more generalizable to diverse populations. Additionally, we adjusted for covariates to minimize confounding factors, thereby enhancing the reliability of our results and their applicability to broader demographics. Finally, stratified analyses allowed us to identify differences among subgroups, considering the characteristics of various populations and further enhancing the generalizability of our conclusions. However, this study has limitations.\u003c/p\u003e\u003cp\u003eDespite the strengths of this study, including the use of a nationally representative large sample and multivariable adjustments to enhance the robustness of the results, several limitations remain. First, as a cross-sectional study, both the exposure (serum vitamin C concentration) and the outcome (kidney stone prevalence) were measured simultaneously, preventing the determination of a temporal sequence and thereby limiting causal inference. Second, although adjustments were made for multiple covariates, potential unmeasured confounders\u0026mdash;such as medication use, genetic susceptibility, and lifestyle factors\u0026mdash;may still influence the results, and their effects cannot be entirely ruled out. Therefore, the findings of this study can only suggest a statistical association between serum vitamin C levels and kidney stone prevalence rather than a causal relationship. Prospective cohort studies or randomized controlled trials are needed in the future to verify the causal basis of this observed U-shaped association. Additionally, some of the data used in this study were derived from questionnaires or interviews, which may introduce a degree of recall bias and should be interpreted with caution.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, this study reveals a significant nonlinear (U-shaped) association between serum vitamin C concentration and the prevalence of kidney stones, with a threshold at 1.69 mg/dL. Although causal relationships cannot be established due to the cross-sectional design, the findings offer new insights for clinical nutrition management. Particularly for high-risk populations such as individuals with obesity, diabetes, or a history of kidney stones, careful control of vitamin C intake may be of reference value. Public health education should further emphasize the principle of \u0026ldquo;moderate supplementation and avoidance of extremes,\u0026rdquo; encouraging the maintenance of appropriate serum vitamin C levels through a balanced diet. Future prospective studies are warranted to validate these findings and to explore whether serum vitamin C concentration can serve as a potential biomarker for identifying individuals at high risk of kidney stone formation, thereby supporting individualized nutritional intervention strategies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003cp\u003eThe protocols of NHANES were approved by the institutional review board of the National Center for Health Statistics, CDC (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.cdc.gov/nchs/nhanes/irba98.htm\u003c/span\u003e\u003cspan address=\"https://www.cdc.gov/nchs/nhanes/irba98.htm\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). NHANES has obtained written informed.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eClinical trial number\u003c/h2\u003e\u003cp\u003enot applicable.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eAuthors' information\u003c/h2\u003e\u003cp\u003eJia-hang Liu, Sheng-Jie Yu, Urology Department, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eJ.L. and S.Y. conceived the study and designed the methodology. J.L., J.T., and H.L. were responsible for data curation and formal analysis. J.L. and X.Y. performed the statistical analysis. J.L. wrote the original draft of the manuscript. All authors (J.T., H.L., X.Y., S.Y.) critically reviewed, edited, and approved the final version of the manuscript. S.Y. supervised the project and had primary responsibility for the final content.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and analyzed in the current study are available at NHANES website:(https://www.cdc.gov/nchs/nhanes/)\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eScales CD Jr, Smith AC, Hanley JM, Saigal CS, Project UDiA (2012). Prevalence of kidney stones in the United States. 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Acta Obstet Gynecol Scand 85(8):960\u0026ndash;965. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1080/00016340500432812\u003c/span\u003e\u003cspan address=\"10.1080/00016340500432812\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Footnotes","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003e\u003cem\u003eNHANES National Health and Nutrition Examination Survey\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e \u003cem\u003eNCHS National Center for Health Statistics\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e \u003cem\u003eUPLC Ultra Performance Liquid Chromatography\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e \u003cem\u003ePIR poverty-to-income ratio\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e \u003cem\u003eBMI body mass index\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e \u003cem\u003eOR the odds ratio\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e \u003cem\u003e95% CI confidence interval\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e \u003cem\u003eROS Reactive Oxygen Species\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Kidney stones, Vitamin C, Kidney disease, NHANES","lastPublishedDoi":"10.21203/rs.3.rs-7978482/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7978482/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eThe relationship between vitamin C levels and the risk of kidney stone formation remains controversial. This study aimed to investigate the association between serum vitamin C concentration and renal calculi occurrence.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA cross-sectional analysis was conducted using data from the 2017\u0026ndash;2018 National Health and Nutrition Examination Survey, comprising 4932 participants. Serum vitamin C concentrations were measured by ultra performance liquid chromatography. The prevalence of kidney stones among participants was determined through self-reported questionnaires. Segmented regression analysis identified a serum vitamin C threshold value of 1.69 mg/dL, the significance of which was confirmed by a log-likelihood ratio test. Subsequently, three logistic regression models were constructed to examine the effects of excess (\u0026ge;\u0026thinsp;1.69 mg/dL) versus non-excess serum vitamin C on kidney stones. Stratified analyses were conducted to evaluate the applicability of these models across different populations.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe prevalence of kidney stones among participants was 10.22%. A U-shaped relationship was observed between serum vitamin C concentration and kidney stone prevalence, with a threshold identified at 1.69 mg/dL. Below this threshold, each unit increase in serum vitamin C concentration decreased kidney stone incidence by 29%. Conversely, above this threshold, kidney stone prevalence was positively correlated with serum vitamin C concentrations.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eThis study identified a nonlinear relationship between serum vitamin C concentration and kidney stone risk, indicating that both excessively high and low serum vitamin C levels are associated with increased risk. These findings underscore the importance of maintaining appropriate serum vitamin C levels for kidney stone prevention; however, further clinical studies are required to validate our conclusions.\u003c/p\u003e","manuscriptTitle":"U-shaped relationship between serum vitamin C concentration and prevalence of kidney stones:a cross-sectional study from NHANES","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-14 01:41:43","doi":"10.21203/rs.3.rs-7978482/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f2770ebf-0363-4e6a-ba69-6883ca5e367e","owner":[],"postedDate":"November 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-15T16:23:11+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-14 01:41:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7978482","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7978482","identity":"rs-7978482","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}