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Abstract
Objectives Most kidney stones contain calcium, which is closely associated with human bone health. Therefore, we aimed to determine the relationship between the history of kidney stones and human bone health. This study examined the associations between lumbar bone mineral density (BMD), serum 25-hydroxyvitamin D (25-OHD) and a history of kidney stones in individuals aged between 30 years and 69 years.
Design and data analysis A multivariate logistic regression model was used to estimate the relationship between lumbar BMD, serum 25-OHD levels and kidney stones in this cross-sectional study. All models incorporated survey sample weights and were adjusted for covariates.
Setting National Health and Nutrition Examination Survey (NHANES) 2011–2018. The exposure and outcomes of this study included the lumbar BMD and presence of kidney stones.
Participants All the 7500 participants for this cross-sectional survey were selected from the NHANES between 2011 and 2018.
Main outcome measures The main outcome of this study was the presence of kidney stones. The interviewers asked the questions on kidney stones while the respondents were at home, using a computer-assisted personal interview system.
Results Lumbar BMD was negatively correlated with a history of kidney stones in all three multivariate linear regression models; the negative association existed in all genders after adjusting for all confounding factors. In the multiple regression analysis, there was an interaction between serum 25-OHD and lumbar BMD (p<0.05) regarding the influence on kidney stones; the negative association between lumbar BMD and kidney stones was more obvious in the higher 25-OHD group (≥50 nmol/L).
Conclusion The study results suggest that maintaining a high lumbar BMD may reduce the incidence of kidney stone formation. Simultaneously, maintaining a high serum 25-OHD level may be more beneficial in preventing the occurrence or recurrence of stones while ensuring a high lumbar BMD.
- urology
- urolithiasis
- urogynaecology
Data availability statement
Data are available upon reasonable request. It is publicly available for people to collect data from the official website for users and researchers worldwide. (www.cdc.gov/nchs/nhanes). Data are available upon reasonable request.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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STRENGTHS AND LIMITATIONS OF THIS STUDY
Use of a large, nationally representative sample of the US population, increasing generalisability.
The content of calcium would affect bone mineral density (BMD), and serum 25-hydroxyvitamin D (25-OHD), in turn, was one of the important factors affecting calcium metabolism. Therefore, we introduced serum 25-OHD, which is closely associated with BMD, to explore whether serum 25-OHD levels affect the protective effect of BMD on kidney stones.
The nature of the cross-sectional study limits the conclusions to associations and cannot assess the causal association of lumbar spine BMD and serum 25-OHD with the history of nephrolithiasis.
In view of the limitations of National Health and Nutrition Examination Survey data, specificity for special groups such as adolescents, pregnant women or those over 70 years was poor.
Due to the lack of data on urinary calcium and the analysis of stone composition, our study has limitations on the related effects of different kinds of stones and urinary calcium excretion.
Introduction
Nephrolithiasis is a common disease that is influenced by multiple factors. After entering the 21st century, the incidence rate of kidney stones showed a significant upward trend, and the male-to-female ratio of 3:1 narrowed.1 2 In a study of the National Health and Nutrition Examination Survey (NHANES) data from 2015 to 2018, the researchers found that the 12-month incidence of kidney stones was significantly higher than that stated in previous reports from the USA. The significantly higher incidence and prevalence of stones are concerning, which have an impact on disease treatment and the allocation of public medical resources.3 Therefore, it is necessary to screen those at high risk of kidney stone disease or recurrence.
Most kidney stones contain calcium,4 which is closely related to human bone health. Therefore, we aimed to determine the relationship between a history of kidney stones and human bone health. As many patients with kidney stones have hypercalciuria, clinicians are concerned that their bone mineral density (BMD) may be reduced, which has inspired several recent studies.5–8 Although many studies have found that the occurrence of kidney stones is associated with a decreased BMD, the results remain inconclusive.
More than 20 years have passed since the last relevant study on the NHANES data.9 The main objective of this study was to measure the relationship between lumbar BMD and kidney stones among adults aged 30–69 years using data from the NHANES (2011–2018). We also introduced serum 25-hydroxyvitamin D (25-OHD), which is closely associated with BMD, to explore whether serum 25-OHD levels affect the protective effect of BMD on kidney stones.
Methods
Data sources
The data used in this study were obtained from the NHANES, which is a research programme designed to assess the health and nutritional status of adults and children in the USA. This was a major project of the National Center for Health Statistics (NCHS). The NHANES is an extensive, consecutive, cross-sectional survey designed to be nationally representative. Researchers worldwide can access data from the NHANES, which is freely available via the internet.
The data used in this study have been deidentified and have been made publicly available (https://www.cdc.gov/nchs/nhanes/index.htm).
In our research, we summarised the data of the NHANES for four 2-year cycles from 2011 to 2018 (lumbar BMD data are missing from 2019 to present). From a total of 39 156 participants, we excluded 24 073 who were younger than 30 years or older than 69 years, 5983 with missing lumbar BMD, 1319 with missing data or refusal to answer the questionnaire about the history of kidney stones, and 281 participants without data on serum 25-OHD, serum calcium and other continuous variables. Finally, 7500 participants were analysed (figure 1).
Flowchart of sample selection from the NHANES 2011–2018. BMD, bone mineral density; NHANES, National Health and Nutrition Examination Survey; 25-OHD, 25-hydroxyvitamin D.
Exposures
Lumbar BMD, an important index for measuring bone quality, reflects the degree of osteoporosis and predicts the risk of fracture. Measurement of lumbar BMD was performed by dual energy X-ray absorptiometry (DXA) scanning, and the software Apex V.3.2 was used in a Hologic discovery type a densitometer (Hologic, Bedford, Massachusetts, USA). The DXA examinations were performed by trained and certified radiologists.
Outcome
The main outcome of this study was the presence of kidney stones. The question used to investigate the presence of kidney stones was Have you ever had kidney stones? Participants can choose from four answers: ‘yes’, ‘no’, ‘refused’ or ‘don’t know’. The trained interviewers asked the questions on kidney stones while the respondents were at home, using a computer-assisted personal interview (CAPI) system. Even though many of NHANES interviewers had prior interviewing experience, they still have to complete a comprehensive training programme. The training included general interview techniques, role-playing exercises, and hands-on interviews with on-site respondents. The NCHS and contractor staff were responsible for the aforementioned training programme. Besides interview administration, the interviewers also participated in a series of cultural competency training sessions to help them recognise and respect cultural differences.
CAPI is a technique used for data collection using portable devices. In the last decade, CAPI has been widely used in social research because of its cost-effectiveness, ease of use and the immediate availability of data.10–12 The usual working form of a CAPI system is that the questionnaire is managed and presented by a computer, and visitors can access and work according to the questions on the computer screen and input the answers given by the interviewees directly into the computer. If the interviewee is unwilling to answer through the interviewer, the interviewee can also input the answer directly into the computer to protect the interviewee’s privacy. When the interview ends, the interviewer directly transmits the questionnaire results to the organiser through the internet. The organiser can then analyse the results immediately after receiving them. The CAPI system was programmed with built-in consistency checks to reduce data entry errors. The CAPI also uses online help screens to assist interviewers in defining the key terms used in the questionnaire.12
Patient and public involvement
Patients or the public were not involved in the design, conduct, reporting or dissemination plans of our research.
Covariates
Among the covariates, we selected age, blood urea nitrogen, serum 25-OHD, serum calcium, serum creatinine, serum glucose, serum phosphorus, serum sodium, serum uric acid, alkaline phosphatase, total cholesterol, total protein, serum potassium, serum triglycerides and body mass index (BMI) as continuous variables; gender, race, physical activities (consist of high-intensity exercise, fitness or recreational activities, such as running or basketball, that cause large increases in respiration or heart rate, lasting at least 10 min), smoking behaviour and ratio of family income to poverty (calculated by dividing family (or individual) income by the poverty guidelines specific to the survey year; if the income reported by the respondent was <$20 000 or ≥$20 000, the value was not calculated; if the family income was reported as a more detailed category, the midpoint of the range was used to compute the ratio; values at or above 5.00 were coded as 5.00 or more because of disclosure concerns; values were not computed if income data were missing) were considered categorical variables. All data were collected from the National Health and NHANES website.
Statistical methods
The weight of the sample analysis package in this study was edited and considered using NCHS V.3.4 (http://www.R-project.org) and EmpowerStats software (http://www.empowerstats.com/). The CI was set at 95%. The association between lumbar BMD, serum 25-OHD levels, and a history of renal calculi was evaluated using multivariable logistic regression models. We constructed three models: model 1, no covariates were adjusted; model 2, only adjusted for age, sex, race and BMI; and model 3, all the covariates listed in table 1 were adjusted. We also performed the subgroup analyses stratified according to sex, lumbar BMD status, and serum 25-OHD status.
Weighted characteristics of the study sample：the cohort of adults aged 30–69 (n=7500)
Results
Table 1 presents the demographic and laboratory data of the participants. Women had a significantly higher lumbar BMD. Participants with higher lumbar BMD had a higher serum creatinine level, BMI, education level, level of physical activity, and ratio of family income to poverty, as well as lower alkaline phosphatase, total cholesterol, serum triglyceride, smoking rate, and stone incidence rate than participants with lower lumbar BMD.
Association between lumbar BMD and kidney stones
We found that lumbar BMD was negatively associated with a history of kidney stone formation in all three models (table 2). The trend in the different lumbar BMD quartile arrays remained significant (p<0.05). This negative association existed in both men and women after adjusting for all confounding factors (OR=0.281, 95% CI 0.131 to 0.601; OR=0.299, 95% CI 0.129 to 0.693) in the subgroup analysis stratified by sex and race, as well as in non-Hispanic whites. In addition, a weighted generalised additive model and smooth curve fitting was used to solve the non-linear relationship and confirm the results (figure 2). This is one of the modules of the EmpowerStats software for statistical applications. This module examines non-linear relationships between outcome variables and risk factors (exposure) using generalised additive models. It is helpful to determine the relationship between non-straightness and whether there is a threshold effect. The outcome variable in this study was dichotomous; therefore, the smooth curve fitting of EmpowerStats software was performed using the gam() function in the mgcv package of R, with the curve fitting term defined by the s() function. The model automatically determined the degree of freedom according to the minimum GCV method.13 After the aforementioned analytical tests, the negative linear relationship between BMD and stone formation remained unchanged.
Association between lumbar BMD (g/cm²) and kidney stones
Association between lumbar BMD and history of kidney stones. Each black point represents a sample. The solid red line represents the smooth curve fit between variables. Blue bands represent the 95% CI from the fit. Gender, age, race, body mass index, education level, blood urea nitrogen, serum calcium, serum creatinine, serum glucose, serum phosphorus, serum sodium, physical activities, smoking behaviour, poverty to income ratio, alkaline phosphatase, total cholesterol, total protein, serum uric acid, serum potassium, and serum triglycerides were adjusted. BMD, bone mineral density.
Interaction between serum 25-OHD and lumbar BMD
According to Holick,14 the Endocrine Society defines vitamin D deficiency as a 25-OHD level of <20 ng/mL (50 nmol/L). Therefore, we divided the serum 25-OHD level into two groups with a tangent point of 50 nmol/L and conducted an interaction analysis. We found an interaction between serum 25-OHD and lumbar BMD (p<0.05) that influenced kidney stones in model 3 (table 3). Furthermore, we performed a stratified analysis of the aforementioned two 25-OHD groups in the multiple regression analysis between lumbar BMD and kidney stones (table 2). The results showed that the negative correlation between lumbar BMD and kidney stones is more obvious (OR=0.249, 95% CI 0.126 to 0.489) in the higher 25-OHD group (≥50 nmol/L).
Interaction between serum 25-OHD (nmol/L) and lumbar BMD (g/cm²)
Discussion
The overall purpose of this study was to explore the relationship between lumbar BMD, serum 25-OHD levels and a history of kidney stones in a nationally representative sample of people of the US population aged 30–69 years. Our results suggest that a low lumbar BMD is correlated with a history of renal calculus both in men and women, and particularly in non-Hispanic white subjects. Although there were some non-linear correlations, the trend was consistent with that of a previous multivariable linear regression analysis. The negative correlation between lumbar BMD and kidney stones is more obvious in the higher serum 25-OHD group (≥50 nmol/L). This finding suggests that maintaining a high lumbar BMD may reduce the incidence of kidney stone formation. Simultaneously, while ensuring a high lumbar BMD, maintaining a high serum 25-OHD level may be more beneficial for preventing the occurrence or recurrence of stones.
In recent years, an increasing number of clinical investigators have noted an association between BMD and history of kidney stones in patients. Consistent with the results of the present study, several studies have also verified, from all aspects, that there is an inverse association between history of kidney stones and BMD.5 15–18 In a 2016 consensus statement, experts recommended that the BMD of patients with hypercalciuric stones or a predisposition to this condition should be measured by DXA.19 This non-invasive examination is convenient and efficient; however, the mechanisms underlying this effect remain unclear. Stones are common in patients with high calcium levels in the urine.20 Hypercalciuria occurs because of a net loss of calcium from the body; therefore, patients usually excrete more calcium than they absorb. Some researchers have speculated that this extra urinary calcium is derived from bone.21 22 In another group, researchers found that sequence variants in the CLDN14 gene may be associated with kidney stones and BMD.23 A study published in 2022 also demonstrated that for adults, the risk of developing kidney stones and osteoporosis increases mutually.24 We have attached the table of this large cohort studies to the supplementary materials as a comparative table for this study (online supplemental material 1).
Supplemental material
Vitamin D plays an important biological role in humans, and vitamin D deficiency is associated with diseases caused by anaemia and oxidative stress.25 Although it has been shown that vitamin D may be responsible for stone formation in selected patients with certain genetic or clinical features,26 27 serum 25-OHD content did not differ between patients with and without stones, according to a previous cross-sectional study.28 29 An interventional study in 2019 found that regular doses of vitamin D supplementation in patients with vitamin D deficiency may not increase the risk of hypercalciuria.30 Several studies have also confirmed that increasing the intake of vitamin D can increase BMD and improve bone quality, with significant beneficial effects on the risk of fractures.31–33 Therefore, for patients with kidney stones or those with a tendency to develop stones, it is reasonable to assume that daily vitamin D supplementation might reduce the risk of stone recurrence or occurrence through the interaction between serum 25-OHD and lumbar BMD. Studies by Larsson et al and Reid et al suggested an insignificant causal relationship between chronically elevated serum 25-OHD concentrations and higher BMD in the general healthy population. Forty nanomoles per litre is a sufficient concentration of serum 25-OHD.34 35 There are also some studies that suggest that vitamin D supplementation at lower amounts is safer in the normal population. The current findings do not support the beneficial effects of high-dose vitamin D supplements on bone health, which may even confer a substantial reduction in BMD, risk of falls, fractures or a small increase in myocardial infarction.36 Excluding people with normal renal function, in kidney transplant recipients, a recent study showed that supplementation with inactive vitamin D did not modify the urinary calcium nor the BMD, Z-score or T-score at lumbar bodies and the femoral neck in kidney transplant recipients.37 According to the current available evidence, the benefits of vitamin D supplementation in humans are more biased towards a ‘U-shaped’ association. Therefore, although daily vitamin D supplementation may be beneficial in patients with kidney stones, treatment measures should be adjusted at any time based on changes in the condition to facilitate a positive balance between risks and benefits.
To make the current findings highly generalisable, the NHANES database aims to provide nationally representative estimates. However, this method has certain limitations. First, the character of this cross-sectional study limits the conclusions to associations and cannot assess the causal association of lumbar spine BMD and serum 25-OHD with a history of nephrolithiasis. Second, due to patients with kidney stones being concentrated in the middle-aged and older age groups and because pregnant women were excluded from DXA examination, individuals aged 30–69 years with a non-pregnant status from the NHANES database were selected for the study. Therefore, the specificity for certain groups, such as adolescents, pregnant women, or those >70 years of age, was poor. Third, as we only assessed BMD at the lumbar spine without introducing BMD at other sites, the present study may have been less clinically representative. Finally, owing to the lack of data on urinary calcium and analysis of stone composition, our study has limitations regarding the related effects of different types of stones and urinary calcium excretion.
Conclusion
Our results suggest that low lumbar BMD is associated with a history of renal calculus, both in men and women and particularly in non-Hispanic white subjects. This finding suggests that maintaining a high lumbar BMD may reduce the incidence of kidney stone formation. At the same time, the negative correlation between lumbar BMD and kidney stones is more obvious in the higher 25-OHD group (≥50 nmol/L), which means that maintaining a high serum 25-OHD level may be more beneficial to prevent the occurrence or recurrence of kidney stones while ensuring a high lumbar BMD.
Data availability statement
Data are available upon reasonable request. It is publicly available for people to collect data from the official website for users and researchers worldwide. (www.cdc.gov/nchs/nhanes). Data are available upon reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants, but the National Health and Nutrition Examination Survey (NHANES) is a publicly available database and all records have been identified. This study was approved by the ethics review board of the National Center for Health Statistics and written informed consents were obtained from each participant. We searched the official website of NHANES and referenced articles from other NHANES databases but could not find any ID.
Acknowledgments
The authors acknowledge the valuable dedication of the research staff and participating subjects throughout the project to National Health and Nutrition Examination Survey.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors XC, SB, ZL, SW, KX and ML: project development, data collection, manuscript editing. LL, JZ and RL data analysis. XC is responsible for the overall content as guarantor.
Funding The 345 Talent Project (grant number M0716) and Joint Plan of Key Research and Development Program of Liaoning Province (grant number 2020JH 2/10300137) were used to support this article.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.