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The association between serum levels of vitamin D and recurrent urinary tract infections in premenopausal women

Open AccessPublished:August 05, 2013DOI:https://doi.org/10.1016/j.ijid.2013.06.007

      Summary

      Objectives

      To examine whether there is any association between serum levels of 25-hydroxy vitamin D (25(OH) vitamin D) and the recurrence of urinary tract infections (UTIs) among premenopausal women.

      Methods

      During a period of 3 years, 93 premenopausal women with a medical history of recurrent UTIs were enrolled from the Infectious Diseases Unit. Cases with recurrent UTIs were compared to 93 age-matched (±5 years) women with no history of recurrent UTI (control group), in terms of serum 25(OH) vitamin D and different risk factors for recurrent UTI. Recurrent UTI was defined as three or more episodes of UTI over a 12-month period.

      Results

      The mean age of women with recurrent UTIs was 43.8 ± 9 years and of controls was 39 ± 10 years (p = 0.839). The mean serum levels of 25(OH) vitamin D among women with recurrent UTIs were significantly lower than those of controls (9.8 ng/ml ± 4 vs. 23 ng/ml ± 6; p < 0.001). Multivariate analysis showed that a serum 25(OH) vitamin D level of < 15 ng/ml (odds ratio 4.00, 95% confidence interval 3.40–4.62; p = 0.001) was associated with recurrent UTIs in premenopausal women.

      Conclusions

      In this retrospective study, we found that recurrent UTIs in premenopausal women are associated with vitamin D deficiency.

      Keywords

      1. Introduction

      Urinary tract infection (UTI) is one of the most commonly acquired bacterial infections in ambulatory and hospitalized populations. Approximately 11% of all women aged ≥18 years in the USA have a UTI each year. The incidence of UTI is highest among women aged 18–24 years, approaching one of five infections per year.
      • Foxman B.
      • Brown P.
      Epidemiology of urinary tract infections: transmission and risk factors, incidence, and costs.
      The incidence of UTIs in Israel is not so well known, as there is a lack of epidemiological studies on this topic. Although, the risk of bladder UTI (cystitis) progression to pyelonephritis is negligible among otherwise healthy women, cystitis has a propensity to recur. Among healthy women aged 18–39 years, the 6-month risk of recurrence following a first UTI is 24%.
      • Foxman B.
      • Gillespie B.
      • Koopman J.
      • Zhang L.
      • Palin K.
      • Tallman P.
      • et al.
      Risk factors for second urinary tract infection among college women.
      Approximately 5% of women with an initial UTI have multiple episodes within a year. Major risk factors for UTI among women aged 18–39 years are engaging in sexual intercourse and having a history of UTI.
      Treating UTIs with antibiotics selects for antibiotic resistance among uropathogens and other bacteria found in and on the human body. In the USA, and worldwide, uropathogens are increasingly resistant to antibiotics.
      • Schito G.C.
      • Naber K.G.
      • Botto H.
      • Palou J.
      • Mazzei T.
      • Gualco L.
      • et al.
      The ARESC study: an international survey on the antimicrobial resistance of pathogens involved in uncomplicated urinary tract infections.
      • Moreira J.R.
      • Siqueira I.C.
      • Alcantara A.P.
      • Guereiro De Moura C.G.
      • De Carvalho W.A.
      • Riley L.
      Antimicrobial resistance of Escherichia coli strains causing community-acquired urinary tract infections among insured and uninsured populations in a large urban center.
      • Zhanel G.G.
      • Hisanaga T.L.
      • Laing N.M.
      • DeCorby M.R.
      • Nichol K.A.
      • Palatnik L.P.
      • et al.
      Antibiotic resistance in outpatient urinary isolates: final results from the North American Urinary Tract Infection Collaborative Alliance (NAUTICA).
      • Alos J.I.
      • Serrano M.G.
      • Gomez-Garces J.L.
      • Perianes J.
      Antibiotic resistance of Escherichia coli from community-acquired urinary tract infections in relation to demographic and clinical data.
      • Karlowsky J.A.
      • Kelly L.J.
      • Thornsberry C.
      • Jones M.E.
      • Sahm D.F.
      Trends in antimicrobial resistance among urinary tract infection isolates of Escherichia coli from female outpatients in the United States.
      Women with recurrent UTIs are prescribed repeated courses of antibiotics both as treatment and as a preventive strategy. Because antibiotic therapy is a major driver of resistance and adversely affects the normal microbiota, preventive strategies that reduce the need for antibiotic therapy are particularly important.
      Vitamin D deficiency has been associated with several adverse health consequences, including autoimmune diseases and infections.
      • Holick M.F.
      Vitamin D deficiency.
      • Arnson Y.
      • Amital H.
      • Shoenfeld Y.
      Vitamin D and autoimmunity: new etiological and therapeutic consideration.
      • Adams J.S.
      • Hewison M.
      Update in vitamin D.
      The results of epidemiological studies have demonstrated the existence of a link between vitamin D deficiency and the increased occurrence of pulmonary tuberculosis and respiratory infections.
      • Nnoaham K.E.
      • Clarke A.
      Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis.
      • Laaksi I.
      • Ruohola J.P.
      • Tuohimaa P.
      • Auvinen A.
      • Haataja R.
      • Pihalajamki H.
      • et al.
      An association of serum vitamin D concentration < 40 nmol/L with acute respiratory tract infection in young Finnish men.
      Recently we showed an association between low serum levels of 25-hydroxy vitamin D (25(OH) vitamin D) and the risk of recurrent bacterial infections.
      • Nseir W.
      • Taha H.
      • Khateeb J.
      • Grosovski M.
      • Assy N.
      Fatty liver is associated with recurrent bacterial infections independent of metabolic syndrome.
      • Nseir W.
      • Mograbi J.
      • Abu-Rahmeh Z.
      • Mahamid M.
      • Abu-Elheja O.
      • Shalata A.
      The association between vitamin D levels and recurrent group A streptococcal tonsillopharyngitis in adults.
      • Mahamid M.
      • Agbaria K.
      • Mahamid A.
      • Nseir W.
      Vitamin D linked to PFAPA syndrome.
      Against this background, we conducted this retrospective study in order to examine whether there is any association between the serum levels of 25(OH) vitamin D and the risk of recurrent UTIs in premenopausal women.

      2. Materials and methods

      2.1 Subjects

      We included all premenopausal women with recurrent UTIs who were followed-up between 2009 and 2011 at the Infectious Diseases Unit of EMMS, a 170-bed primary care hospital in Nazareth, Israel. Premenopausal women aged 20–52 years who had not received antibiotic prophylaxis for recurrent UTIs, including post-coital, were included. The exclusion criteria were: (1) pregnancy, and (2) chronic renal failure (creatinine clearance test <30 ml/min), a chronic liver disease, a malignancy with life expectancy less than 1 year, HIV infection, connective tissue diseases, permanent urinary catheter, urinary tract stent, nephrostomy tube, urinary incontinence, neurogenic bladder, asymptomatic bacteriuria, kidney malformations, kidney stones, gynecological problems, organ transplant, chronic use of corticosteroid therapy, vitamin D supplementation, and substance abuse.
      Control cases were premenopausal women with no medical history of UTI, randomly collected from the Medicine Clinic and Employee Health Clinic, EMMS, who were age-matched ±5 years; the same exclusion criteria were used. The matching was performed on a group, rather than individual level. For each case of recurrent UTI we recruited one control case. The study was approved by the review board of EMMS.

      2.2 Study design

      This was a retrospective study aimed at examining the association between serum 25(OH) vitamin D levels and recurrent UTIs in premenopausal women. In order to assess this, we compared the two groups of premenopausal women – with and without recurrent UTIs – in term of: diabetes mellitus (DM), maternal history of recurrent UTIs, oral contraceptive use, probiotics, cranberry juice consumption, sexual intercourse, and serum levels of 25(OH) vitamin D.

      2.3 Clinical and laboratory data

      Information concerning medical conditions and drug therapy, and the results of laboratory analyses, were extracted from the medical charts of each subject in the two groups. (In general, every subject who visits the Infectious Diseases Unit/Medicine Clinic/the Employee Health Clinic, completes a standard questionnaire at every visit concerning their medical condition, drug therapy, family history of different diseases, systemic bacterial infections, and results of laboratory analyses, including urinalysis and urine culture.) The results of chemistry analysis, including fasting blood glucose, hemoglobin A1c (HbA1c), serum creatinine, serum calcium, and a complete blood count, were collected from the medical charts. Serum 25(OH) vitamin D levels were measured in winter and summer seasons (at least twice a year) for all patients visiting our units. Serum 25(OH) vitamin D levels were measured using a commercial kit (IMM, Bensheim, Germany), by enzyme immunoassay (EIA). The normal range of serum 25(OH) vitamin D levels is 30–50 ng/ml.

      2.4 Definitions

      UTI was defined by clinical signs of dysuria and the urgency and frequency of urination (cystitis), and the presence of fever, chills, and/or loin pain (pyelonephritis). Bacterial UTIs included cystitis, urethritis, and acute pyelonephritis.
      • Hooton T.M.
      • Stamm W.E.
      Diagnosis and treatment of uncomplicated urinary tract infection.
      Recurrent UTI was defined as a symptomatic UTI following the resolution of a previous UTI and of three or more symptomatic episodes over a 12-month period.
      • O’Reilly M.
      Recurrent urinary tract infection.
      All case patients had to have recurrent UTIs including one or more culture-confirmed UTI; the UTI could be a case of re-infection or relapse. Re-infection refers to a new infection, i.e. the urine shows no growth after the previous infection, but the same organism grows again at 2 weeks after treatment, or a different strain is grown at any time. A relapse refers to a UTI caused by the bacterial strain from a focus inside the urinary tract within 2 weeks of treatment. Normal levels of serum creatinine are 0.67–1.17 mg/dl and of serum calcium are 8.1–10.4 mg/dl. We defined vitamin D insufficiency as levels of 25(OH) vitamin D 20–30 ng/ml, and vitamin D deficiency as levels of 25(OH) vitamin D <20 ng/ml.

      2.5 Statistical analysis

      WinSTAT (Kalamia, Cambridge, MA, USA) was used for data handling and analysis. Mean values, standard deviations (SDs), and p-values were calculated. The Chi-square test was performed for categorical variables, and the Student's t-test was used for continuous variables. Spearman rank correlation and univariate regression analysis were used to determine the strengths of the relationships between the different risk factors and recurrent UTIs. A risk factor associated with a p-value of <0.05 in the univariate analysis was used for further analysis. A multivariate analysis was performed to determine the association between the risk factors and recurrent UTIs. Statistical significance was set at 5%.

      3. Results

      Of 265 women followed-up in the Infectious Diseases Unit for UTIs during the study period, 93 premenopausal women with recurrent UTIs met the inclusion criteria. One hundred and seventy-two subjects were excluded because of: postmenopausal (n = 41), no recurrent UTI (n = 60), pregnancy (n = 7), chronic renal failure (n = 19), liver cirrhosis (n = 7), malignancy with life expectancy <1 year (n = 16), permanent urinary catheter (n = 7), kidney stones (n = 5), chronic steroid use (n = 3), and vitamin D use (n = 7). Table 1 shows the clinical and laboratory parameters of the cases with recurrent UTIs and the controls. No significant difference was found between the cases and controls in terms of age, DM, maternal history of recurrent UTIs, oral contraceptive use, probiotics, sexual intercourse, and indoor/outdoor activities. No subjects in the two study groups were using cranberry juice as prophylaxis. However, compared to the control group, serum 25(OH) vitamin D levels were significantly lower in the cases (9.8 ng/ml ± 4 vs. 23 ng/ml ± 6, respectively; p < 0.001). The lowest 25(OH) vitamin D level was 4 ng/ml, which was found in one subject who suffered from recurrent UTIs (at least 6 episodes/year); the highest level was 46 ng/ml, which was found in one subject in the control group. All study participants were of the same race.
      Table 1A comparison of certain clinical and laboratory parameters between cases with recurrent UTIs and controls
      Cases with recurrent UTI

      (n = 93)
      Controls

      (n = 93)
      p-Value
      Age, years, mean ± SD43.8 ± 939 ± 10NS
      Diabetes mellitus, n (%)26 (28%)20 (21.5%)NS
      Maternal history of recurrent UTI, n (%)13 (14%)6 (6.5%)NS
      Use of oral contraceptives, n (%)2 (2.2%)4 (4.3%)NS
      Use of probiotics, n (%)2 (2.2%)6 (6.5%)NS
      Sexual intercourse ≥1 per week (%), n (%)45 (48%)54 (58%)NS
      Serum 25(OH) vitamin D, ng/ml, mean ± SD9.8 ± 423 ± 6<0.001
      Indoor, n (%)82 (88%)78 (84%)NS
      UTI, urinary tract infection; SD, standard deviation; NS, not significant.
      Multivariate analysis showed that a maternal history of recurrent UTIs (odds ratio (OR) 1.60, 95% confidence interval (CI) 1.40–2.60; p = 0.05), no use of probiotics (OR 1.94, 95% CI 1.61–2.82; p = 0.04), and serum 25(OH) vitamin D <15 ng/ml (OR 4.00, 95% CI 3.40–4.62; p = 0.001), were associated with recurrent UTIs in premenopausal women. The multivariate analysis results are shown in Table 2.
      Table 2Results of the multivariate analysis of recurrent UTI among premenopausal women
      VariableOR (95% CI)p-Value
      Age >35 years1.55 (1.10–2.82)NS
      Maternal history of recurrent UTI1.60 (1.40–2.60)0.05
      No use of probiotics1.94 (1.61–2.82)0.04
      25(OH) vitamin D of <15 ng/ml4.0 (3.40–4.62)0.001
      Sexual intercourse ≥1 per week1.25 (0.75–2.2)NS
      UTI, urinary tract infection; OR, odds ratio; CI, confidence interval; NS, not significant.

      4. Discussion

      In this retrospective study, we found that vitamin D deficiency in premenopausal women was independently associated with recurrent UTIs.
      The mechanism(s) that link vitamin D deficiency with recurrent UTI are unknown. There are many host defense factors in the urinary tract, such as the Tamm–Horsfall protein, lipocalin, and lactoferrin, which offer some protection from infection.
      • Raffi H.S.
      • Bates J.M.
      • Laszik Z.
      • Kumar S.
      Tamm–Horsfall protein acts as a general host-defense factor against bacterial cystitis.
      Infections of the urinary tract induce epithelial cells to produce cathelicidin LL-37, protecting against bacterial infection.
      • Chromek M.
      • Slamova Z.
      • Bergman P.
      • Kovacs L.
      • Podracka L.
      • Ehren I.
      • et al.
      The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection.
      Vitamin D is a potent stimulator of antimicrobial peptides including cathelicidin LL-37 in innate immunity.
      • Chun R.F.
      • Adams J.S.
      • Hewison M.
      Back to the future: a new look at “old” vitamin D.
      Recently, Hertting et al. observed a significant increase in cathelicidin in response to vitamin D in biopsy samples of urinary bladder infected by uropathogenic Escherichia coli.
      • Hertting O.
      • Holm A.
      • Luthje P.
      • Brauner H.
      • Dyrdak R.
      • Jonasson A.F.
      • et al.
      Vitamin D induction of the human antimicrobial peptide cathelicidin in the urinary bladder.
      In humans, the production of cathelicidin and some defensins depends upon vitamin D levels, particularly during the infection process.
      • Wang T.T.
      • Nestel F.P.
      • Bourdeau V.
      • Nagai Y.
      • Wang Q.
      • Liao J.
      • et al.
      Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression.
      Previous studies have shown the importance of vitamin D for innate immunity in defending against bacterial infections, mainly by increasing the neutrophilic motility and phagocytic function.
      • Bikle D.D.
      Vitamin D and the immune system: role in protection against bacterial infection.
      • Lorente F.
      • Fontan G.
      • Jara P.
      • Casas C.
      • Garcia-Rodriguez M.C.
      • Ojeda J.A.
      Defective neutrophil motility in hypovitaminosis D rickets.
      We consider that these abovementioned mechanisms could explain why women with low levels of serum 25(OH) vitamin D are prone to recurrent UTIs. However, more studies are needed to investigate the mechanisms involved in the pathogenesis of vitamin D deficiency and predisposition to bacterial infections.
      In case–control studies, Scholes et al.
      • Scholes D.
      • Hooton T.M.
      • Roberts P.L.
      • Stapleton A.E.
      • Gupta K.
      • Stamm W.E.
      Risk factors for recurrent urinary tract infection in young women.
      and Hooten
      • Hooton T.M.
      Recurrent urinary tract infection in women.
      reported that a history of UTI in the mother is associated with 2–3-fold increase in risk of UTI in her daughters. A maternal history of UTI suggests that inherited factors may be important in some cases of recurrent UTI.
      • Kunin C.M.
      The natural history of recurrent bacteriuria in schoolgirls.
      Otherwise, this risk factor could reflect other shared environmental factors, or behaviors present in both mothers and daughters. The contribution of genetics to UTIs has been discussed in several studies.
      • Svanborg-Eden C.
      • Briles D.
      • Hagberg L.
      • McGhee J.
      • Michalec S.
      Genetic factors in host resistance to urinary tract infection.
      • Lundstedt A.C.
      • Leijonhufvud I.
      • Ragnarsdottir B.
      • Karpman D.
      • Andersson B.
      • Svanborg C.
      Inherited susceptibility to acute pyelonephritis: a family study of urinary tract infection.
      Lundstedt et al. showed that susceptibility to acute pyelonephritis is inherited and that low CXCR1 expression might predispose to acute pyelonephritis.
      • Lundstedt A.C.
      • Leijonhufvud I.
      • Ragnarsdottir B.
      • Karpman D.
      • Andersson B.
      • Svanborg C.
      Inherited susceptibility to acute pyelonephritis: a family study of urinary tract infection.
      In our study we found that a maternal history of UTI was associated with 1.6-fold increase in the risk of recurrent UTI.
      Lactobacilli are the dominant bacteria of the vaginal flora and possess antimicrobial properties that regulate the urogenital microbiota. Incomplete cure and recurrence of genitourinary infections leads to a shift in the local flora from a predominance of lactobacilli to coliform uropathogens. The use of Lactobacillus-containing probiotics to restore the commensal vaginal flora has been proposed for the treatment and prophylaxis of recurrent UTIs.
      • Barrons R.
      • Tassone D.
      Use of Lactobacillus probiotics for bacterial genitourinary infections in women: a review.
      Recently, a meta-analysis was done regarding Lactobacillus for the prevention of UTIs in women.
      • Grin P.M.
      • Kowalewska P.M.
      • Alhazzan W.
      • Fox-Robichaud A.E.
      Lactobacillus for preventing recurrent urinary tract infections in women: meta-analysis.
      Data from 127 patients in two studies were included. Results showed probiotic strains of Lactobacillus to be safe and effective in preventing recurrent UTIs in adult women. In our study we found no use of probiotics to be associated with recurrent UTIs in premenopausal women. However, more randomized clinical trials (RCTs) are needed to examine the efficacy of probiotics as prophylaxis in recurrent UTIs.
      Our study has several limitations: being a retrospective study, including a relatively small number of subjects, having incomplete data concerning body mass index, and not investigating the role of vitamin D receptors, cathelicidin, and the innate immune system.
      In conclusion, vitamin D deficiency was found to be associated with recurrent UTIs in premenopausal women. RCTs are needed to assess if a correction of serum levels of 25(OH) vitamin D could prevent the recurrence of UTIs.
      Conflict of interest: The authors declare no conflicts of interest.

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