Wang et al. Nutrition Journal (2016) 15:32 DOI 10.1186/s12937-016-0148-y RESEARCH Association between serum vitamin D levels and the risk of kidney stone: evidence from a meta-analysis Hai Wang *, Libo Man, Guizhong Li, Guanglin Huang and Ning Liu Abstract Open Access Background: Many epidemiological studies have conducted to evaluate the association between serum vitamin D levels and the risk of kidney stone. The aim of this study was to summarize the evidence from epidemiological studies between them. Methods: Pertinent studies were identified by a search of PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure (CNKI) and China Biology Medical literature up to July 2015. Standardized mean difference (SMD) was conducted to combine the results. Random-effect model was used. Publication bias was estimated using Egger s regression asymmetry test. Results: Seven articles involving 451 kidney stone cases and 482 controls were included in this meta-analysis. Our pooled results suggested that kidney stone patients had a significantly higher serum vitamin D level compared with controls [summary SMD = 0.65, 95 % CI = 0.51, 0.79, I 2 = 97.0 %]. The associations were also significant both in Europe [SMD = 0.35, 95 % CI = 0.17, 0.53] and in Asia [SMD = 1.00, 95 % CI = 0.76, 1.25]. No publication bias was found. Conclusions: Our analysis indicated that serum vitamin D level in kidney stone patients was significantly higher than that in non-kidney stone controls, both in Europe and Asia populations. Keywords: Serum, Vitamin D level, Kidney stone, Meta-analysis Introduction Kidney stone disease is common in the general population with an estimated prevalence of about 3 5 %infemalesand 10 15 % in males [1]. The most common type (about >80 %) is the calcium-based kidney stone, and high urine calcium excretion is a strong risk factor for stone formation [2, 3]. Prior studies had shown that a higher concentration of the active vitamin D metabolite, 1,25-dihydroxyvitamin D, is associated with increased urinary calcium excretion [4, 5], which could lead to increase the risk of stone formation. Despite vitamin D played an important role of in maintaining bone health, as well as a variety of other physiologic functions [6], many clinicians are reluctant to treat vitamin D deficiency or insufficiency in kidney stone formers because of the theoretical risk of increasing urinary calcium excretion. This reluctance likely derives from the fact that vitamin D is often cited as a risk factor for kidney stones [7]. To date, a number of epidemiologic studies have been published exploring the relationship between serum vitamin D level and kidney stone risk. The aim of this meta-analysis was to (1) assess the association of serum vitamin D levels in kidney stone patients compared with the non-kidney stone controls; and (2) assess heterogeneity and publication bias among the studies we analyzed. Methods Literature search Two authors independently searched the databases of PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure (CNKI) and China Biology Medical literature for relevant articles published before July 2015 using the following search terms: cholecalciferol OR ergocalciferol OR vitamin* AND kidney stone OR * Correspondence: wanghai150701@163.com Department of Urology, Beijing Jishuitan Hospital, No. 31, East Xinjiekou Street, Xicheng District, 100035 Beijing, PR China 2016 Wang et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Wang et al. Nutrition Journal (2016) 15:32 Page 2 of 5 Urolithiasis OR nephrolithiasis with written in English or Chinese. In addition, we reviewed references of obtained articles. Disagreements between the two authors were resolved by consensus with a third author. Study selection Studies were eligible for analysis if they met the following criteria: (1) the studies were in case control or cohort design or cross-sectional design or randomized controlled trials; (2) the exposure was serum vitamin D level; (3) the end point was kidney stone; (4) available mean and standard deviation (SD) of serum vitamin D level or data provided from which mean and SD could be calculated; and (5) unrelated case and control groups or exposed and unexposed groups in cohort study and all subjects from the same temporally and geographically defined underlying population. Accordingly, the following exclusion criteria were also used: (1) reviews and (2) repeated or overlapped publications. Data extraction We extracted data from the included articles, with particular regards to: the last name of the first author, publication year, country of region, study design, study population, age for cases and controls, number of cases and controls, the mean ± SD of serum vitamin D levels, and statistical adjustment for the main confounding or mediating factors. Statistical analysis Pooled measure was performed on the standardized mean difference (SMD) with 95 % CI to assess the strength of association between serum vitamin D level and risk of kidney stone. Random-effects model was used to combine study-specific SMD (95 % CI), which considers both within-study and between-study variation [8]. The Q test and I 2 of Higgins and Thompson [9] were used to assess heterogeneity among included studies. I 2 describes the proportion of total variation attributable to between-study heterogeneity as opposed to random error or chance, with suggested thresholds for low (25 50 %), moderate (50 75 %) and high (>75 %) heterogeneity, respectively [10]. Meta-regression and subgroup analyses were performed to assess the potentially important covariates that might exert substantial impact on between-study heterogeneity [11]. We used the Egger regression asymmetry test to evaluate the publication bias [12]. Sensitivity analysis was conducted to describe how robust the pooled estimator was to removal of individual studies [13]. An individual study is suspected of excessive influence, if the point estimate of its omitted analysis lies outside the 95 % CI of the combined analysis. All statistical analyses were performed using Stata 12.0 (Stata Corp, College Station, Texas, USA). Two-tailed P 0.05 was accepted as statistically significant. Results Literature search A total of 3558 citations were retrieved from the electronic databases. After initial screening of titles and abstracts using the aforementioned criteria, 45 articles were identified for full-text review (all the 45 articles were cited as a Additional file 1). Of these, 38 were further excluded, leaving seven eligible articles (Fig. 1). Hence, seven articles [14 20] involving 451 kidney stone cases and 482 controls were included in our final meta-analysis. Two studies were come from Iran, one from United States, one from Netherlands, one from Germany, one from Italy and one from Sweden. The characteristics of these included studies arepresentedintable1. Serum vitamin D level and kidney stone risk Five of these included studies reported an increased risk of kidney stone for serum vitamin D levels in kidney stone patients compared with controls, while no significant association was reported in two studies. Our pooled results suggested that kidney stone patients had a significantly higher serum vitamin D level compared with non-kidney stone controls [summary SMD = 0.65, 95 % CI = 0.51, 0.79], with high between-study heterogeneity detected (I 2 = 97.0 %, P heterogeneity =0.000) (Fig. 2). Fig. 1 The flow diagram of screened, excluded, and analyzed publications
Wang et al. Nutrition Journal (2016) 15:32 Page 3 of 5 Table 1 Characteristics of studies on the association between serum vitamin D levels and kidney stone risk Study, Country kidney stones Study Kidney stone Controls year assessed type N (Male) Age (Mean ± SD) N (Male) Berlin et al. [14] Fallahzadeh et al. [15] Giannini et al. [16] Meta-regression and subgroup analysis As seen in Fig. 2, evidence of high between-study heterogeneity (I 2 =97.0 %, P heterogeneity = 0.000) was found in the pooled results. In order to explore the high between-study heterogeneity founded in the analysis, univariate meta-regression with the covariates of publication year, study design and geographic locations were performed. However, no significant findings were found in the above-mentioned analysis. For the subgroup analyses by study design, the association was also significant in case control studies Serum vitamin D: Mean ± SD (ng/ml) Age (Mean ± SD) Serum vitamin D: Mean ± SD (ng/ml) Sweden Symptomatic Case-control 38 (34) Na 26.2 ± 1.6 32 (16) Na 17.6 ± 0.9 Iran Ultrasounds Case-control 36 (24) 8.4 ± 4.7 months 33.85 ± 14.73 36 (22) 8.7 ± 4.7 months 18.26 ± 7.43 Italy Symptomatic Case-control 25 (16) 41.2 ± 2.4 39.6 ± 2.6 15 (7) 49.0 ± 3.7 28.9 ± 1.8 Jarrar et al. [17] Germany Ultrasounds Case-control 57 (35) 54.92 ± 23.32 53.65 ± 27.46 44 (22) 53.34 ± 18.51 48.3 ± 30.8 Leaf et al. [18] Netelenbos et al. [19] Shakhssalim et al. [20] United States Ultrasounds Randomized 29 (22) 48 ± 12 35 ± 10 29 (22) 48 ± 12 17 ± 6 controlled trials Netherlands Symptomatic Case-control 160 (106) 43 ± 14 55 ± 23 217 (147) 39 ± 11 53 ± 22 Iran Symptomatic Case-control 106 (106) 43.4 ± 6.9 127 ± 40 109 (109) 38.4 ± 6.9 93 ± 35 SD standard deviation; Na not available [SMD = 0.57, 95 % CI = 0.43, 0.72; I 2 =97.2 %] of serum vitamin D levels in kidney stone patients compared with the controls. There is only one study was randomized controlled trials design, and no pooled results for other study design was combined. In subgroup analyses of geographic locations, when we restricted the analysis to Europe and Asia, the associations were significant both in European populations [SMD = 0.35, 95 % CI = 0.17, 0.53; I 2 = 98.1 %] and in Asian populations [SMD = 1.00, 95 % CI = 0.76, 1.25; I 2 = 51.4 %]. Fig. 2 The forest plot of the association between serum vitamin D levels and kidney stone risk
Wang et al. Nutrition Journal (2016) 15:32 Page 4 of 5 Sensitivity analysis and publication bias Sensitivity analysis showed that no individual study had excessive influence on the association of serum vitamin D levels with the risk of kidney stone. Egger s regression asymmetry test (P =0.596) showed no evidence of significant publication bias between serum vitamin D levels and kidney stone risk. Discussion In this study, data were available with 451 kidney stone cases and 482 controls for the analysis. This work provided convincing evidence that serum vitamin D level in kidney stone patients was significantly higher than that in non-kidney stone controls. The associations were also significant both in Europe and in Asia populations. In our study, significant between-study heterogeneity was found between serum vitamin D levels and kidney stone risk. Previous paper [21] had reported that heterogeneity is common in the meta-analyses. To explore the potential sources of between-study heterogeneity is therefore an essential component of meta-analysis. The high degree of heterogeneity might have arisen from publication year, study design and geographic locations. Therefore, we used meta-regression to explore the causes of heterogeneity by covariates. However, no covariate had significant impact on the high betweenstudy heterogeneity among those mentioned above. Considering the pooled meta-analysis was fraught with the problem of heterogeneity, subgroup analyses by study design and geographic locations to explore the source of heterogeneity. However, between-study heterogeneity persisted in some of the subgroups, suggesting the presence of other unknown confounding factors. Other environment variables, as well as their possible interaction, may well be potential contributors to the heterogeneity observed. As a meta-analysis of published studies, our findings showed some advantages. First, a highlight of this study was that we found a significant association between serum vitamin D levels and the risk of kidney stone. Second, the current study included more kidney stone cases and controls; this may derive a more precise estimation of the relationship between serum vitamin D and kidney stone risk. Third, no significant publication bias was detected in this meta-analysis. There are some limitations in this meta-analysis should be concerned. First, six of the seven studies were case control design and only one study was randomized controlled trials design. Although case control studies may suffer from recall bias and selection bias, case control studies are important methods in etiology research. More studies with other study design are wanted in the future studies. Second, as a meta-analysis of epidemiologic studies, we cannot rule out that individual studies may have failed to control for potential confounders, which may introduce bias in an unpredictable direction. Third, for the subgroups of geographic locations, the associations were significant both in Europe and in Asia between serum vitamin D levels and kidney stone risk. Only one study was conducted from United States. Thus, we did not combine the results for other populations. Due to this limitation, the results are applicable to Europe and Asia, but cannot be extended to other populations. More studies originating in other countries are required to investigate the association between serum vitamin D levels and kidney stone risk. Finally, betweenstudy heterogeneity was high in the pooled analysis, but the heterogeneity was not successfully explained by the subgroup analysis and meta-regression. However, other environment variables, as well as their possible interaction may be potential contributors to this diseaseeffect unconformity. Conclusions Findings from this meta-analysis suggest that serum vitamin D level in kidney stone patients was significantly higher than that in controls. Additional file Additional file 1: The potentially relevant articles identified for full-text review. (DOCX 74 kb) Competing interests The authors declare that they have no competing interests. Authors contributions Conceived and designed the study: HW. Performed the study: HW, LM, GL, GH and NL. Analyzed the data: HW and LM. Wrote the paper: HW. Critically revised the manuscript: HW. All authors read and approved the final manuscript. Received: 17 September 2015 Accepted: 17 March 2016 References 1. Stamatelou KK, Francis ME, Jones CA, Nyberg LM, Curhan GC. Time trends in reported prevalence of kidney stones in the United States: 1976 1994. Kidney Int. 2003;63:1817 23. 2. Tang J, Chonchol MB. Vitamin D and kidney stone disease. Curr Opin Nephrol Hypertens. 2013;22:383 9. 3. Sakhaee K, Maalouf NM, Kumar R, Pasch A, Moe OW. Nephrolithiasisassociated bone disease: pathogenesis and treatment options. Kidney Int. 2011;79:393 403. 4. Shen FH, Baylink DJ, Nielsen RL, Sherrard DJ, Ivey JL, Haussler MR. Increased serum 1,25-dihydroxyvitamin D in idiopathic hypercalciuria. J Lab Clin Med. 1977;90:955 62. 5. Broadus AE, Insogna KL, Lang R, Ellison AF, Dreyer BE. Evidence for disordered control of 1,25-dihydroxyvitamin D production in absorptive hypercalciuria. N Engl J Med. 1984;311:73 80. 6. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266 81. 7. Worcester EM, Coe FL. Clinical practice. Calcium kidney stones. N Engl J Med. 2010;363:954 63. 8. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177 88.
Wang et al. Nutrition Journal (2016) 15:32 Page 5 of 5 9. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539 58. 10. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557 60. 11. Higgins JP, Thompson SG. Controlling the risk of spurious findings from meta-regression. Stat Med. 2004;23:1663 82. 12. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629 34. 13. Tobias A. Assessing the in fluence of a single study in the meta-analysis estimate. Stata Tech Bull. 1999;47:15 7. 14. Berlin T, Bjorkhem I, Collste L, Holmberg I, Wijkstrom H. Relation between hypercalciuria and vitamin D3-status in patients with urolithiasis. Scand J Urol Nephrol. 1982;16:269 73. 15. Fallahzadeh MH, Zare J, Al-Hashemi GH, Derakhshan A, Basiratnia M, Arasteh MM, et al. Elevated serum levels of Vitamin D in infants with urolithiasis. Iran J Kidney Dis. 2012;6:186 91. 16. Giannini S, Nobile M, Castrignano R, Pati T, Tasca A, Villi G, Pellegrini F, D'Angelo A. Possible link between vitamin D and hyperoxaluria in patients with renal stone disease. Clin Sci (Lond). 1993;84:51 4. 17. Jarrar K, Amasheh RA, Graef V, Weidner W. Relationship between 1,25- dihydroxyvitamin-d, calcium and uric acid in urinary stone formers. Urol Int. 1996;56:16 20. 18. Leaf DE, Korets R, Taylor EN, Tang J, Asplin JR, Goldfarb DS, Gupta M, Curhan GC. Effect of vitamin D repletion on urinary calcium excretion among kidney stone formers. Clin J Am Soc Nephrol. 2012;7:829 34. 19. Netelenbos JC, Jongen MJ, van der Vijgh WJ, Lips P, van Ginkel FC. Vitamin D status in urinary calcium stone formation. Arch Intern Med. 1985;145:681 4. 20. Shakhssalim N, Gilani KR, Parvin M, Torbati PM, Kashi AH, Azadvari M, Golestan B, Basiri A. An assessment of parathyroid hormone, calcitonin, 1,25 (OH)2 vitamin D3, estradiol and testosterone in men with active calcium stone disease and evaluation of its biochemical risk factors. Urol Res. 2011;39:1 7. 21. Munafo MR, Flint J. Meta-analysis of genetic association studies. Trends Genet. 2004;20:439 44. Submit your next manuscript to BioMed Central and we will help you at every step: We accept pre-submission inquiries Our selector tool helps you to find the most relevant journal We provide round the clock customer support Convenient online submission Thorough peer review Inclusion in PubMed and all major indexing services Maximum visibility for your research Submit your manuscript at www.biomedcentral.com/submit