The association between obesity and urinary tract infection

European Journal of Internal Medicine 24 (2013) 127–131

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Original article

The association between obesity and urinary tract infection Walid Saliba a, b,⁎, Ofra Barnett-Griness a, Gad Rennert a, c a

Department of Community Medicine and Epidemiology, Carmel Medical Center, Clalit Health Services, and Bruce Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel b Internal Medicine C, Ha'emek Medical Center, Afula, Israel c Department of Epidemiology and Disease Prevention, Office of the Chief Physician, Clalit Health Services Headquarters, Tel Aviv, Israel

a r t i c l e

i n f o

Article history: Received 5 September 2012 Received in revised form 9 November 2012 Accepted 13 November 2012 Available online 29 November 2012 Keywords: Urinary tract infection Obesity BMI Vitamin D 25(OH)D Diabetes mellitus

a b s t r a c t Background: Few studies examined the relationship between obesity and urinary tract infection (UTI), showing inconsistent results. This study aims to examine the association between obesity and UTI, and to assess whether this association is independent of diabetes mellitus and 25(OH)D level. Methods: Using the computerized database of the largest healthcare provider in Israel, we identified a cohort of subjects ≥18 years old with available BMI and serum 25(OH)D level measurements between January 2009 and December 2009. The cohort was followed for the first UTI diagnosis from January 2010 through June 2011. Cox proportional hazard model was used to test the relationship between obesity and UTI. Results: During follow-up, 25,145/110,736 (22.7%) females, and 4032/42,703 (9.4%) males had UTI. The crude HR for UTI in those with BMI≥ 50 compared to BMIb 25 was 2.54 (95% CI, 1.50–4.30) in males and 1.39 (1.14–1.69) in females. After adjusting for age, 25(OH)D level, and history of diabetes mellitus, the HR for UTI in those with BMI≥ 50 compared to BMIb 25 was 2.38 (1.40–4.03) in males and 1.25 (1.03–1.52) in females. The HR for those in the lowest quartile of serum 25(OH)D compared to the highest quartile was 1.23 (1.13– 1.35) in males and 0.98 (0.95–1.02) in females. The HR for subjects with diabetes was 1.23 (1.16–1.32) in males, and 1.25 (1.20–1.28) in females. Conclusions: Obesity is independently associated with UTI particularly in males. Low serum 25(OH)D levels are associated with increased risk of UTI in males. © 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction Obesity has become one of the most important public health problems in the United States [1]. Obesity is associated with increasing mortality and morbidity from a variety of diseases including; hypertension, dyslipidemia, metabolic syndrome, cardiovascular diseases, impaired vitamin D status, and diabetes mellitus [2–4]. Previous studies also suggest that obesity may be associated with urinary tract infection (UTI), but the results were inconsistent. Only few studies have addressed this issue, and were either small with short follow-up, or limited to diabetic or postoperative patients [5–8]. In addition, no adjustment was done for vitamin D status and diabetes mellitus, two conditions that are associated with both obesity [2,4], and increased risk of infection and UTI [9,10], which potentially could confound the association between obesity and UTI. This study aims to examine the association between obesity and UTI in order to confirm the results of previous studies, and to assess

whether this association is independent of 25(OH)D levels and diabetes mellitus. 2. Materials and methods 2.1. Study population and data source The study population was drawn from among the insurees of Clalit Health Services (CHS), the largest not-for-profit health care provider in Israel, covering more than half of the Israeli population. Using the computerized database of CHS, we identified a cohort of subjects ≥18 years old with available BMI and serum 25(OH)D level measurements between January 2009 and December 2009. In subjects who had more than one 25(OH)D or more than one BMI measurements during this period, the result of the most recent measurement was used (n = 153,439 subjects, 110,736 females, and 42,703 males). 2.2. Follow up

⁎ Corresponding author at: Department of Community Medicine and Epidemiology, Carmel Medical Center, 7 Michal St., Haifa 34362, Israel. Tel.: +972 4 825 0474; fax: +972 4 834 4358. E-mail address: [email protected] (W. Saliba).

The cohort was followed from the index date January 1st, 2010 until the first diagnosis of UTI, death, moving from the CHS to another health maintenance organization (HMO), or until June 31st, 2012, whichever occur first. During the follow-up period 4436 (2.9%) subjects died, and

0953-6205/$ – see front matter © 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejim.2012.11.006

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1405 (0.91%) subjects moved from the CHS to another healthcare provider. These subjects were censored at the date of their death or the date of their movement to another healthcare provider.

2.3. Study variables For the purpose of this study we considered only lower urinary tract infection as defined by ICD-9 coding [6], including; acute cystitis (ICD-9, 595.0), unspecified cystitis (ICD-9, 595.9), and urinary tract infection (ICD-9, 599.0). Asymptomatic bacteriuria was not considered for the purpose of this study. We will use the terminology “UTI” to indicate lower urinary tract infection through the manuscript. Body mass index (BMI) was calculated (weight (kilograms)/ height2 (meters)) and was classified into five categories (b25, 25 to 29.9, 30 to 39.9, 40 to 49.9, and ≥50 kg/m2). Serum 25(OH)D was used to assess vitamin D status and was classified into quartiles (Q1: b37.7, Q2: 37.7 to 55.3, Q3: 55.4 to 72.6, and Q4: > 72.6 nmol/L).

2.4. The 25(OH)D assay 25(OH)D was tested using the LIAISON® 25-OH Vitamin D TOTAL assay (DiaSorin), a competitive two-step chemiluminescence assay. The measuring range is 4.0–150 ng/mL (10–375 nmol/L), the analytical sensitivity b 1.0 ng/mL (2.5 nmol/L), and the functional sensitivity b4.0 ng/mL (10 nmol/L). The intra-assay precision is up to 5%, and the inter-assay precision is up to 15%. The specificity for 25-OH Vitamin D2 is 104%, and for 25-OH Vitamin D3 is 100%. Performance characteristics of the Vitamin D assay were checked in the method evaluation process done by Clalit Health Services and were compatible to the manufacturer-generated data. The accuracy of the measurements in the individual laboratory is confirmed by in-house daily quality control (QC) monitoring and by periodic external QC program (DEQAS). 2.5. Statistical analysis Continuous data are presented as means with standard deviations (SD). Categorical variables are presented as proportions. The unpaired

Table 1 Characteristics of the study participants stratified by gender; CHS cohort, Israel. All Variable

Gender Males Females Ethnicity Jews Arabs History of DM 25(OH)D Mean ± SD Age Mean ± SD UTI

Body mass index (BMI) (kg/m2)

P value

All (n = 153,439)

b25 (n = 54,845)

25–29.9 (n = 54,710)

30–39.9 (n = 39,350)

40–49.9 (n = 4,108)

≥50 (n = 426)

27.8% 72.2%

25.4% 74.6%

33.1% 66.9%

25.3% 74.7%

14.9% 85.1%

16.4% 83.6%

88.0% 12.0% 23.1%

91.0% 9.0% 12.1%

89.1% 10.9% 23.6%

83.6% 16.4% 35.1%

76.2% 23.8% 46.0%

76.1% 23.9% 42.3%

56.4 ± 25.6

60.5 ± 26.9

67.0 ± 24.5

51.3 ± 24.2

43.5 ± 22.5

41.9 ± 23.8

59.3 ± 17.3 19%

54.6 ± 19.7 18.1%

62.0 ± 15.8 18.6%

62.2 ± 14.5 20.5%

59.1 ± 14.1 22.1%

58.6 ± 14.9 27.0%

b0.001

b0.001

b0.001 b0.001 b0.001 b0.001

Males Variable

Ethnicity Jews Arabs History of DM 25(OH)D Mean ± SD Age Mean ± SD UTI

Body mass index (BMI) (kg/m2)

P value

All males (n = 42,703)

b25 (n = 13,947)

25–29.9 (n = 18,105)

30–39.9 (n = 9,969)

40–49.9 (n = 612)

≥50 (n = 70)

86.1% 13.9% 29.2%

88.2% 11.8% 18.9%

86.8% 13.2% 29.4%

82.4% 17.6% 42.0%

79.4% 26.6% 50.5%

85.7% 14.3% 38.6%

58.0 ± 24.6

60.8 ± 26.2

58.5 ± 23.8

53.8 ± 23.4

46.0 ± 20.6

46.7 ± 23.7

59.7 ± 18.0 9.4%

56.1 ± 21.1 8.6%

61.9 ± 16.6 9.3%

61.2 ± 14.9 10.6%

55.8 ± 14.9 13.4%

57.6 ± 19.2 20.0%

b0.001

b0.001 b0.001 b0.001 b0.001

Females Variable

Ethnicity Jews Arabs History of DM 25(OH)D Mean ± SD Age Mean ± SD UTI DM; diabetes mellitus.

Body mass index (BMI) (kg/m2)

P value

All females (n = 110,73)

b25 (n = 40,898)

25–29.9 (n = 36,605)

30–39.9 (n = 29,381)

40–49.9 (n = 3,496)

≥50 (n = 356)

88.7% 11.3% 20.8%

92.0% 8.0% 9.8%

90.2% 9.8% 20.7%

84.0% 16.0% 32.8%

75.7% 24.3% 45.2%

74.2% 25.8% 43.0%

55.8 ± 25.9

60.4 ± 27.1

56.3 ± 24.8

50.4 ± 24.4

43.0 ± 22.8

41.0 ± 23.8

59.2 ± 17.1 22.7%

54.1 ± 19.2 21.3%

62.1 ± 15.4 23.3%

62.5 ± 14.4 23.8%

59.6 ± 13.8 23.6%

58.8 ± 14.0 28.4%

b0.001

b0.001 b0.001 b0.001 b0.001

W. Saliba et al. / European Journal of Internal Medicine 24 (2013) 127–131

Student t test was used to compare means between two groups, and the analysis of variance (ANOVA) was used to compare means between more than two groups. Comparisons of categorical variables between groups were performed with the chi-square test. Time to UTI was calculated from date of study initiation (01.January.2010) until the first diagnosis of UTI. Survival curves were constructed using the Kaplan–Meier methods, and curves were compared with the log rank test. Proportional hazard regression analysis was used to assess the association between time to UTI and BMI adjusting for age, serum 25(OH)D level, and presence of diabetes mellitus before the initiation of the study. P value for trend was calculated by including the BMI groups as continuous variable in the model. The association was estimated with hazard ratio (HR) with 95% confidence interval (95% CI), using the lowest BMI group as reference group. Two way interactions were assessed by including the product of the variables in the multivariate model. For all analyses, P value of less than 0.05 for 2-tailed tests was considered statistically significant. All statistical analyses were performed using SPSS 18.0 (SPSS Inc., Chicago).

129

A

BMI<25 BM 25-29.9 BM 30-39.9 BM 40-49.9

BM 50

3. Results Overall, during the study follow-up 29,177/153,439 (19.9%) of the study participants were diagnosis with UTI. Females were more likely to be diagnosed with UTI 25,145/110,736 (22.7%) compared to 4032/ 42,703 (9.4%) of males (P b 0.001). 110,736 (72.2%) of the study participants were females. The mean age was 59.3 ±17.3 years and was similar between males and females. The characteristics of the study participants by the BMI category are presented in Table 1 for all participants, and separately for males and females. Compared to subjects in lower BMI groups, subjects in the higher BMI groups were more likely to be females, Arabs, and to have history of diabetes mellitus. The mean serum 25(OH)D level decreased with increasing BMI, and the proportion of subjects diagnosed with UTI increased with increasing BMI (Table 1). The proportion of subjects with event free survival decreased with increasing BMI both in males (log rank, P b 0.001), and females (log rank, P b 0.001) (Fig. 1). In the proportional hazard regression model, the crude HR for UTI was 2.54 (1.50–4.30) for males in the highest BMI group compared to the normal weight males, and was 1.39 (1.14–1.69) in females (P for interaction = 0.001) (Table 2). On the multivariate proportional hazard model which included; BMI categories, serum 25(OH)D quartiles, age, and history of diabetes mellitus (Table 3), the adjusted HR for UTI was 2.38 (1.40–4.03) for males in the highest BMI group compared to the normal weight males, and 1.25 (1.03–1.52) in females. However, after adjustment for multiple comparisons, a statistical significance was not reached in females as evidenced by global P value of 0.187 (Table 3). The strength of association increased with increasing BMI in males but not in females (P for trend 0.002 versus 0.186). On multivariate analyses, the HR for UTI was 1.23 (1.13–1.35) for males in the lowest quartile of serum 25(OH)D (b37.7 nmol/L) compared to the highest quartile (>72.6 nmol/L). While in female levels ≤ 72.6 were associated with a very mild decrease in UTI risk compared to higher levels. The HR for UTI was 1.23 (1.16–1.32) in diabetic males, and 1.24 (1.20–1.28) in diabetic females. Age had stronger effect in males compared to females, the HR for 10 years increase in age was 1.44 (1.41–1.47) and 1.08 (1.07–1.09) respectively (Table 3). 4. Discussion In this study we have shown that in males, obesity was independently associated with UTI showing a significant dose response relationship. In females, there was a non significant tendency to increased risk of UTI which was confined to BMI ≥ 50 kg/m2. These results are consistent with previous studies [5,6]. Ribera et al. have shown that obesity was associated with UTI only in men [6].

Time (weeks)

B

BMI<25 BM 25-29.9 BM 30-39.9 BM 40-49.9 BM 50

Time (weeks) Fig. 1. Kaplan–Meier curve for UTI according to BMI category, A in males, B in females; CHS cohort, Israel.

Semines et al. showed that the association of obesity with UTI was significant in males and had a dose effect pattern increasing with increasing with BMI, while the relationship in females was smaller and was observed only for certain BMI ranges [5]. Obese subjects have higher risk of postoperative urinary tract infection [7]. However, one study did not found an association with BMI and UTI [8]. The persistent unchanged strength of association between obesity and UTI after adjusting for diabetes mellitus and serum 25(OH)D, also suggests that the association is not mediated through these two risk factors, and that obesity increase the risk of UTI through another mechanism. Being the association of obesity and UTI confined to males, points that male factors are involved. A plausible explanation is the direct association of obesity with prostate volume [11–15], a surrogate marker of benign prostate hyperplasia (BPH), which in turns is associated with increased risk of UTI [16,17]. Abdominal obesity can affect benign prostatic enlargement by raising estrogen, as well as free and total estradiol, while lowering total testosterone and serum protein binding levels [12]. The elevated estrogen/

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Table 2 Univariate Cox's proportional hazard model for urinary tract infection (UTI) stratified by gender; CHS cohort, Israel. Variables

Gender Males (n=42,703) Females (n=110,736) HR (95% CI) HR (95% CI)

BMI b25 kg/m2 25–29.9 kg/m2 30–39.9 kg/m2 40–49.9 kg/m2 ≥50 kg/m2 Global P value (4df) P for trend 25(OH)D quartile Q1: (b37.7 nmol/L) Q2: (37.7–55.3 nmol/l) Q3: (55.4–72.6 nmol/L) Q4: (>72.6 nmol/L) Global P value (3df) P for trend Diabetes Mellitus Age (for 10 years increase)

P for interaction

0.001 Reference 1.07 (0.99–1.15) 1.22 (1.13–1.33) 1.58 (1.26–1.97) 2.54 (1.50–4.3) b0.001 b0.001

Reference 1.10 (1.07–1.13) 1.13 (1.10–1.17) 1.13 (1.05–1.21) 1.39 (1.14–1.69) b0.001 b0.001

1.16 (1.07–1.27) 0.95 (0.87–1.03) 0.96 (0.88–1.05) Reference b0.001 0.004 1.66 (1.56–1.77) 1.45 (1.42–1.48)

0.96 (0.93–0.99) 0.95 (0.92–0.98) 0.95 (0.92–0.98) Reference 0.006 0.038 1.34 (1.31–1.38) 1.09 (1.08–1.10)

b0.001

b0.001 b0.001

testosterone ratio associated with obesity might increase the stromal/ epithelial cell ratio in benign prostatic hyperplasia nodules, obesity may also increase sympathetic activity which may also contribute to the development of BPH [11–13]. In this study we have also shown that risk of UTI was increased by 23% in males with serum 25(OH)D b 37.7 nmol/L compared to levels > 72.6 nmol/L. While in female levels ≤ 72.6 were associated with a very mild decrease in UTI risk compared to higher levels. Vitamin D deficiency could influence the development of BPH because the active form of vitamin D is a regulator of prostatic cell growth through antiproliferative effects [18]. In the NHANES 2005–2006, serum 25(OH)D b 50 nmol/L were associated with lower urinary tract symptoms in US men [19]. However, a study in Korean patients did not found correlation between prostate size and vitamin D [15]. Low serum 25(OH)D levels may also increase UTI risk through its effect on cathelicidin, a human antimicrobial peptide which is expressed and secreted by the urinary bladder epithelial cells and protect the urinary tract from infection. It has been shown that when urinary bladder cells were infected with uropathogenic Escherichia coli, a

Table 3 Multivariatea Cox's proportional hazard model for urinary tract infection (UTI) stratified by gender; CHS cohort, Israel. Variables

Gender Males (n=42,703) Females (n=110,736) HR (95% CI) HR (95% CI)

BMI b25 kg/m2 25–29.9 kg/m2 30–39.9 kg/m2 40–49.9 kg/m2 ≥50 kg/m2 Global P value (4df) P for trend 25(OH)D quartile Q1: (b37.7 nmol/L) Q2: (37.7–55.3 nmol/l) Q3: (55.4–72.6 nmol/L) Q4: (>72.6 nmol/L) Global P value (3df) P for trend Diabetes mellitus Age (for 10 years increase)

Reference 0.93 (0.86–1.00) 1.07 (0.98–1.17) 1.62 (1.29–2.03) 2.38 (1.40–4.03) b0.001 0.002

Reference 1.02 (0.98–1.05) 1.02 (0.98–1.05) 1.00 (0.93–1.08) 1.25 (1.03–1.52) 0.187 0.186

1.23 (1.13–1.35) 1.03 (0.94–1.12) 0.99 (0.91–1.08) Reference b0.001 b0.001 1.23 (1.16–1.32) 1.44 (1.41–1.47)

0.98 (0.95–1.02) 0.95 (0.92–0.98) 0.95 (0.92–0.98) Reference 0.006 0.447 1.24 (1.20–1.28) 1.08 (1.07–1.09)

significant increase in cathelicidin expression was observed in response to vitamin D supplementation [20]. Another interesting finding of our study is the increased risk of UTI in diabetic patients, which was similar between males and females. Previous studies have shown that UTI and asymptomatic bacteriuria are more common in diabetic women compared to women without diabetes [6,21,22]. However, no increase in UTI and asymptomatic bacteriuria was found in diabetic men compared to men without diabetes [6,23,24]. Factors that may contribute to the increased susceptibility to UTI in diabetes include; decreased antibacterial activity due to “sweet” urine, defects in neutrophil function, and increased adherence to uroepithelial cells which is the most likely mechanism [24]. This study has several limitations; it relies on a computerized database that was not specifically designed for the present study. Our study may suffer from selection bias to the reliance on subjects who have available measurements of BMI and serum 25(OH)D levels and could reflect a sicker population. In addition the diagnosis of UTI was based on the ICD-9 codes, we could not ascertain the results of urine cultures, whether a urine culture was obtained from subjects, whether the diagnosis was done on clinical ground only, and whether the diagnosis is merely a diagnosis of asymptomatic bacteriuria. This study may also be affected by detection bias, as obese subjects are more likely to be under medical care, and hence, may be more likely to be diagnosed with UTI leading to differentially overestimation of UTI in this group of subjects. However, detection bias is expected to occur to the same degree both in obese males and females, but the association of obesity with UTI was almost confined to males, making the possibility of detection bias less likely. Cause-and-effect relationship can not be proven from this observational study, obesity may be a marker of known and unknown risk factors that may confound the association of obesity with UTI. More studies are needed to confirm our findings; this will be best done by randomized clinical trials by assessing the risk of UTI with weight reduction. In conclusion BMI is directly associated with UTI particularly in males. Low serum 25(OH)D levels are associated with increased risk of UTI in males. Future prospective and interventional studies are needed to confirm these findings. Learning points • Obesity is independently associated with urinary tract infection particularly in males • Low serum 25(OH)D levels are associated with increased risk of UTI in males.

P for interaction

Conflict of interests

b0.001

No conflict of interest or financial disclosures were reported by the authors of this paper. References

0.001

b0.001 b0.001

a Variable included in the model; BMI categories, serum 25(OH)D quartile, age, and history of diabetes mellitus.

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