Asymptomatic Bacteriuria in Women with Diabetes: Influence of Metabolic Control

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1 MAJOR ARTICLE Asymptomatic Bacteriuria in Women with Diabetes: Influence of Metabolic Control Mario Bonadio, 1 Elisabetta Boldrini, 2 Giovanna Forotti, 2 Elena Matteucci, 2 Armando Vigna, 1 Stefano Mori, 1,2 and Ottavio Giampietro 2 1 Infectious Diseases Section and 2 Metabolic Unit, Department of Internal Medicine, University-Hospital, Pisa, Italy We screened 228 women with diabetes for bacteriuria during the period of January 1997 through December 2000 at Pisa General Hospital (Pisa, Italy). A control group of 146 women without diabetes was also evaluated. The frequency of significant bacteriuria was 17.5% (40 of 228) among women with diabetes and 18.5% (27 of 146) among women in the control group. Seven (13.5%) of 52 and 33 (18.8%) of 176 women with type 1 and in type 2 diabetes, respectively, had significant bacteriuria. The presence of higher glycated hemoglobin levels was the only significant risk factor for significant bacteriuria in women with type 2 diabetes. A similar frequency of bacteriuria in women with and women without diabetes was found. Severe impairment of metabolic control of type 2 diabetes increases the risk of acquiring asymptomatic bacteriuria. Urinary tract infection (UTI) is classically assumed to be a clinically relevant problem for patients with diabetes [1]. Severe complications of UTI occur virtually only in patients with diabetes. In 1935, Sharkey and Root [2] reported purulent UTI in 18% of the necroscopy specimens obtained from patients with diabetes. Robbins and Tucker [3] reported that, at autopsy, 4.5% of patients with diabetes had papillary necrosis. Some individuals with diabetes may present with a distressing picture showing definite progression of pyelonephritis characterized by evidence of systemic infection, local extension of the infection (e.g., renal and perinephric abscesses), septicemia, and severe impairment of metabolic control, which may become too difficult to manage. For these reasons, diabetes has long been considered to be a predisposing factor for UTI. However, since the Received 1 August 2003; accepted 18 November 2003; electronically published 27 February Presented in part: 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, December 2001 (L-1354). Reprints or correspondence: Dr. Mario Bonadio, Infectious Diseases Section, University of Pisa, Ospedale S. Chiara, via Roma 55, Pisa, Italy (m.bonadio@ int.med.unipi.it.). Clinical Infectious Diseases 2004; 38:e by the Infectious Diseases Society of America. All rights reserved /2004/ E1$15.00 concept of significant bacteriuria was introduced, the reported data on the prevalence of asymptomatic bacteriuria (ASB) among patients with diabetes appear to be conflicting [4 8]. Many UTIs are asymptomatic, especially in women. Unlike men with or without diabetes (among whom similar rates of UTI have been documented in most studies), several recent reports have noted a higher prevalence of ASB among women with diabetes than among women without diabetes [8 11]. Early studies, however, showed no difference between the frequency of both asymptomatic and symptomatic bacteriuria among women with diabetes, compared with women in matched control groups [12 15]. Various risk factors for ASB in women with diabetes have been suggested (e.g., age, sexual intercourse, disease duration, quality of metabolic control of disease, and status of diabetic complications [16 20]). Most reports, however, included only a small number of patients, often without distinguishing between those with type 1 and those with type 2 diabetes. Consequently, we decided to investigate the frequency of ASB in a large study involving women with diabetes. In addition, all women with diabetes were evaluated to verify whether there is a correlation between bacteriuria and the following suggested risk factors: the known duration of diabetes, the actual metabolic control of diabetes, morphological and functional aspects of the kidneys, Asymptomatic Bacteriuria and Diabetes CID 2004:38 (15 March) e41

2 and the presence of microangiopathy (i.e., retinopathy and nephropathy). PATIENTS AND METHODS Two hundred twenty-eight women aged years with diabetes mellitus type 1 (52 patients) or type 2 (176 patients) were enrolled in our study from January 1997 through December These women were patients at the Metabolic Clinic of the Department of Internal Medicine, Pisa University Hospital (Pisa, Italy). A randomly selected control group of 146 outpatient women without diabetes (most of whom were receiving treatment at a cardiology clinic) was also evaluated in the same period. None of these women underwent bladder catheterization during the 2 months before enrollment. Most patients in the control group had some underlying medical illnesses (e.g., coronary heart disease, high blood pressure, and chronic obstructive pulmonary disease). To exclude patients with diabetes from the group without diabetes, we confirmed that they had neither diabetes nor glycosuria. All patients were screened for significant bacteriuria, which was defined as the presence of at least 10 5 cell forming units/ ml in 1 culture of a clean-voided midstream urine specimen. Within 60 min after voiding, quantitative urine culture was performed by means of a dip-slide method, which has been demonstrated to be reliable in many studies [21]. Urine samples were also streaked on MacConkey agar and calcium nutrient blood agar for better confirmation of microorganism growth. Identification of urine isolates was performed using conventional methods, and the in vitro susceptibility to antimicrobial drugs was tested by the Kirby-Bauer disk diffusion method. The presence of 110 leukocytes per high-power field in the sediment of centrifuged urine was defined as pyuria. Diagnosis of diabetes mellitus was made in accordance with the criteria of the American Diabetes Association [22]. The following parameters were evaluated in women with diabetes: age, duration of diabetes, glycated hemoglobin (HbA1c) level (% of total hemoglobin), microalbuminuria (urinary albumin excretion rate [UAER]), glomerular filtration rate (GFR), kidney size (longitudinal diameter), and presence of retinopathy. HbA1c was measured once on the same morning that the urine culture was performed. The HbA1c level was measured using high-performance liquid chromatography, the UAER was determined by immunonephelometry, the GFR was measured by g-camera imaging of injected 99m Tc diethylenetriaminepentaacetic acid (DTPA), and kidney size was determined by measuring the longitudinal diameters of both kidneys on a conventional renal ultrasonograph. An unpaired Student s t test was used for statistical analysis of the results. Data are expressed as mean values ( SD). RESULTS Table 1 summarizes the most important demographic and clinical features of the women with diabetes in this study. The age of the patients was years ( and years for those with type 1 and 2 diabetes, respectively; P!.001). The duration of the disease was years ( and years, respectively; P!.01). The HbA1c level, which reflects the impairment of metabolic control of the disease, was 9.2% 1.9% of total hemoglobin ( 9.5% 2.2% and 9.0% 1.9% of total hemoglobin, respectively; P p NS). The GFR was ml/min ( and ml/min, respectively; P!.001). The UAER was mg/min ( and mg/min, respectively; P p NS). As expected, the women with type 2 diabetes were older and had a longer known duration of disease than did women with type 1 diabetes. The women with type 1 diabetes had higher GFR values than did those with type 2 diabetes. These findings closely agree with the age- Table 1. Demographic and clinical features of diabetic women who were evaluated for asymptomatic bacteriuria. Characteristic Type 1 (n p 52) Diabetes type Type 2 (n p 176) Total (n p 228) P a Age, years Duration of diabetes, years HbA1c level, % of total Hb NS Glomerular filtration rate, ml/min Urinary albumin excretion rate, mg/min NS NOTE. Data are expressed as mean values SDs. Hb, hemoglobin; HbA1c, glycated hemoglobin; NS, not significant. a Obtained using an unpaired Student s t test. e42 CID 2004:38 (15 March) Bonadio et al.

3 dependent decrease in renal function. The age of the women without diabetes was years. The rate of significant bacteriuria (as defined by criteria described above) was 13.5% (7 of 52) among women with type 1 diabetes, 18.8% (33 of 176) among those with type 2 diabetes, and 18.5% (27 of 146) among those in the control group. Pyuria was recognized in 35 of 40 bacteriuric women with diabetes and in 30 of 33 bacteriuric women without diabetes. Table 2 shows the correlation between some suggested risk factors and ASB in women with type 2 diabetes. The age of nonbacteriuric and bacteriuric women was and years, respectively ( P p NS). The known duration of diabetes was and years, respectively ( P p NS), and the GFR was and ml/min, respectively ( P p NS). The UAER was and mg/min, respectively ( P p NS), and the kidney size was and mm, respectively ( P p NS). The HbA1c level was 8.9% 1.8% and 9.6% 2%, respectively; the difference in this instance was statistically significant ( P!.05). Of the 176 women with type 2 diabetes, only 166 underwent ophthalmologic evaluation. Retinopathy was present in 44.0%; 52, 14, and 7 women had background, preproliferative, and proliferative retinopathy, respectively. No significant differences were found between bacteriuric and nonbacteriuric women with type 1 diabetes with regard to age, diabetes duration, GFR, kidney size, UAER, and HbA1c level. Escherichia coli was the causative agent of ASB in 27 (67.5%) of 40 women with and in 17 (63.0%) of 27 women without diabetes. E. coli strains recovered from women with and from those without diabetes showed similar resistance patterns to the antimicrobial drugs; 12% vs. 15% were resistant to ampicillin, 8% vs. 10% were resistant to nitrofurantoin, 8% vs. 11% were resistant to cotrimoxazole, and 8% vs. 5% were resistant to ciprofloxacin. DISCUSSION In this study, we found that the rate of ASB among women with type 2 diabetes is similar to that among women without diabetes (18.8% vs. 18.5%). Early studies demonstrated no differences in the prevalence of ASB between women with and women without diabetes, but, in the majority of the most recent studies, a 2 3-fold increase in the frequency of ASB among women with diabetes has been reported. The 3 largest studies in which 400, 341, and 1072 outpatient women with diabetes were evaluated showed ASB rates of 9.5%, 9.1%, and 7.9%, respectively [23, 24]. In these studies, the diagnostic criterion for ASB was 2 consecutive positive urine culture results. A prevalence of ASB of 26% in a group of 378 women with diabetes has been reported, with a diagnostic criterion for ASB of 1 2 urine specimens with 10 5 unit-forming colonies per ml of urine [11]. The reason we observed a higher rate of ASB in the control group may have been because we enrolled patients with only 1 positive urine culture result. The reason we observed similar rates of ASB in women with and in women without diabetes could be explained by considering some of the epidemiological features of the nondiabetic (control) population. Our control group comprised women without diabetes, most of whom were receiving treatment at a cardiology clinic. We did not assess whether they had additional risk factors for bacteriuria. The women without diabetes had no history of recent bladder catheterization. The age of the women without diabetes was similar to that of women with type 2 diabetes ( vs years). In some of the studies mentioned Table 2. Risk factors for asymptomatic bacteriuria in women with type 2 diabetes. Risk factor Presence of bacteriuria No (n p 143) Yes (n p 33) Age, years NS Duration of diabetes, years NS HbA1c level, % of total Hb !.05 Glomerular filtration rate, ml/min NS Urinary albumin excretion rate, mg/min NS Kidney size, mm b NS NOTE. Data are expressed as mean values SDs. Hb, hemoglobin; HbA1c, glycated hemoglobin; NS, not significant. a Obtained using an unpaired Student s t test. b Measured by adding the left and right longitudinal diameters. P a Asymptomatic Bacteriuria and Diabetes CID 2004:38 (15 March) e43

4 above, the control group probably was comprised of patients with less-severe illness. We observed a similar rate of ASB among patients with and patients without diabetes, possibly because most of our patients had disease that was well controlled (fasting blood glucose levels, mg/dl) and because they were receiving treatment at the time of study enrollment. In the present study, however, a significant correlation was found between HbA1c level and ASB in women with type 2 diabetes. This means that a significant impairment of the longterm metabolic control of the disease increases the risk of developing ASB. Previous studies did not find any significant correlation between hyperglycemia and glycosuria severity, HbA1c level, and ASB [18 20]. In another study of 110 patients with diabetes, a significant association between bacteriuria, pyuria, and HbA1c levels was found [25]. Suggested host mechanisms in the pathogenesis of ASB in patients with diabetes are presence of glycosuria, defective neutrophil function, and increased adherence to uroepithelial cells. In vitro studies showed that glycosuria enhances the growth of different E. coli strains [26]. However, this was not confirmed by in vivo studies, which failed to show a higher prevalence of ASB among diabetic patients with glycosuria, compared with those without glycosuria [27]. Many studies involving women with diabetes have reported an association between ASB and long-term complications of diabetes, such as retinopathy, nephropathy, and neuropathy [24]. The bladder dysfunction due to diabetic neuropathy could play a role in the prevalence of ASB among women with diabetes and in the natural history of UTI [23]. In the present study, however, we were not able to evaluate bladder function. Our results on the association between ASB and HbA1c levels differ from those obtained in other, similar studies. This can be explained by hypothesizing that our bacteriuric women with type 2 diabetes had a bladder dysfunction associated with diabetic autonomic neuropathy more frequently than did bacteriuric women with diabetes in other studies. This last circumstance is classically linked to impaired metabolic control, as suggested elsewhere [28]. Two other results are of note in our study. The first is that no significant differences regarding the function and size of the kidneys were found between bacteriuric and nonbacteriuric women with diabetes. This observation is in agreement with a recent study [29] that found no differences in renal function deterioration between women with type 2 diabetes who had or did not have ASB. In addition, it is important to emphasize the fact that studies performed in schoolgirls without diabetes and with ASB have demonstrated that minimal renal damage occurs in patients with ASB compared with nonbacteriuric control subjects [30]. An old study showed that UTI, in the absence of other predisposing factors, does not lead to renal damage [31]. We also found that the prevalence of microalbuminuria was similar among women with type 2 diabetes who had or did not have ASB. Microalbuminuria has been used as an early marker of diabetic nephropathy. We are performing a followup study with our patients to verify whether or not ASB per se influences the development or the worsening of diabetic nephropathy. The fact that causative organisms of urinary infection and their susceptibility patterns to the most common antimicrobials were similar between women with and women without diabetes means that both groups of patients had similar risk factors for developing antimicrobial resistance at the time of entry into the study. One of our previous studies demonstrated similar results [32]. In conclusion, the data obtained in our study of a large cohort of women with type 2 diabetes demonstrate that it is difficult to prove that ASB is more frequent among women with diabetes than among those without diabetes. In addition, we have demonstrated that impairment of metabolic control of diabetes as revealed by an increase in the HbA1c level increases the risk of developing ASB. References 1. Baldwin AD, Root HF. Infections of the upper urinary tract in the diabetic patient. N Engl J Med 1940; 223: Sharkey TP, Root HF. Infections of urinary tract complicating diabetes mellitus. JAMA 1935; 104: Robbins SC, Tucker AW. The cause of death in diabetes. N Engl J Med 1944; 231: Huvos A, Rocha J. Frequency of bacteriuria in patients with diabetes mellitus. N Engl J Med 1959; 261: Rengards RT. Asymptomatic bacteriuria in sixty-eight diabetic patients. Am J Med Sci 1960; 239: Szucs S, Cserhati, Csapo G, Balazs V. 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