Albumin Excretion Rate Is Not Affected by Asymptomatic Urinary Tract Infection

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1 Clinical Care/Education/Nutrition O R I G I N A L A R T I C L E Albumin Excretion Rate Is Not Affected by Asymptomatic Urinary Tract Infection A prospective study CRISTINA HERNÁNDEZ, MD RAFAEL SIMÓ, MD OBJECTIVE The aim of the study was to evaluate whether asymptomatic urinary tract infection (UTI) significantly influences the level of albumin excretion rate (AER) in diabetic patients. RESEARCH DESIGN AND METHODS We screened prospectively for UTI and AER in 765 type 2 diabetic subjects. AER was determined before and after antimicrobial therapy in those patients in whom an asymptomatic UTI was diagnosed (n 59). To interpret the clinical significance of AER changes, the coefficient of biological variation (CVb) of the AER (CVb-AER) was assessed in a control group of type 2 diabetic patients without UTI (n 56). RESULTS AER did not change after antimicrobial treatment either in the whole group of patients with UTI (pre: 13.8 g/min [ ] vs. post: 8.5 g/min [ ]; P 0.1) or in those patients in whom the infection was eradicated (pre: 11.7 g/min [ ] vs. post: 7.1 g/min [ ]; NS). The CVb-AER was 64% in the control group and was inversely correlated with AER (r 0.44; P 0.001). The decrease of AER after antimicrobial therapy (55%) did not exceed the biological variation of AER (64%). Finally, UTI did not significantly influence the classification of diabetic patients as normo- or microalbuminuric. CONCLUSIONS Asymptomatic UTI does not increase AER in type 2 diabetic patients. Therefore, our results suggest that testing for UTI is not necessary when AER is measured in diabetic patients. The urinary albumin excretion rate (AER) is the main parameter used in diabetic patients to clinically evaluate early diabetic nephropathy (1). Apart from its use in monitoring renal functional loss, AER is considered an indicator of endothelial dysfunction as well as an independent marker for cardiovascular disease (2 4). However, there are many confounding factors that should be taken into account when interpreting the results of the AER measurement, one of which is Diabetes Care 27: , 2004 the inherent variability of AER, which clearly makes several tests advisable in the follow-up of diabetic patients (5). Urinary tract infection (UTI) is another confounding factor that theoretically may influence the AER. An American Diabetes Association position statement (1) indicates that UTI can cause transient elevations in AER. For this reason, it is considered necessary to rule out UTI when assessing AER. In addition, it has been recommended that the AER be determined after resolution of From the Diabetes Research Unit, Division of Endocrinology, Hospital Universitari Vall d Hebron, Barcelona, Spain. Address correspondence and reprint requests to Dr. Rafael Simó, Diabetes Research Unit, Division of Endocrinology, Hospital Universitari Vall d Hebron, Pg. Vall d Hebron, , Barcelona, Spain. rsimo@hg.vhebron.es. Received for publication 9 February 2004 and accepted in revised form 10 April Abbreviations: AER, albumin excretion rate; CVb, coefficient of biological variation; UTI, urinary tract infection. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances by the American Diabetes Association. UTI to avoid falsely elevated results (1). However, although this statement could be recommendable in symptomatic or complicated UTI, there is a lack of solid evidence to support this guideline in asymptomatic UTI. Moreover, given that asymptomatic UTI is common in diabetic women (6,7), the current practice is both time and resource consuming. On this basis, the aim of the present study was to evaluate prospectively whether asymptomatic UTI influences the level of AER in diabetic patients. For this purpose, AER was determined before and after antimicrobial therapy in patients in whom a UTI was diagnosed. Because the high biological variability in AER could lead to a misinterpretation of the results, this confounding factor was also considered. RESEARCH DESIGN AND METHODS From January 2002 to January 2003, we prospectively screened all type 2 diabetic subjects attending our primary care outpatient diabetic clinic for UTI and AER every Wednesday and Thursday (n 765, 334 men and 431 women). The exclusion criteria considered were macroalbuminuria (AER 200 g/ min), renal failure (serum creatinine mol/l), cardiovascular disease, and symptomatic UTI. To assess the past and present evidence of cardiovascular disease, a standardized cardiovascular questionnaire and a careful physical examination, including an ankle-arm blood pressure and a 12-lead electrocardiogram (Minnesota codes), were used. Patients who smoked and who started or modified antihypertensive treatment during the follow-up were excluded. The patients maintained uniform daily habits (diet and physical exercise) for the duration of the study. In addition, no significant changes in the pharmacological treatment were implemented during the course of the protocol. AER was determined in 24-h urine samples by the turbidimetric end point DIABETES CARE, VOLUME 27, NUMBER 7, JULY

2 Urinary infection and albumin excretion rate Table 1 Characteristics of diabetic patients included in the study method (Olympus; Olympus Diagnostica, Hamburg, Germany). The coefficient of analytical variation was 3.5%. Microalbuminuria was defined as an AER of g/min in at least two of the last three urine samples collected before the inclusion. Normoalbuminuria was defined as an AER 20 g/min. Midstream urine specimens were collected into a sterile container, and the samples were cultured for bacterial growth, quantification, and antimicrobial sensitivity. A diagnosis of UTI was made if 10 5 colony-forming units/ml of a pathogen grew in the urine culture. We defined contaminated urine as that having the presence of at least three different microorganisms in the urine specimen. Patients with contaminated urine specimens were excluded. Antimicrobial therapy was indicated in patients with UTI according to antimicrobial sensitivity, and a second determination of AER with another urine culture was performed 2 4 days after finishing the antimicrobial treatment. To assess AER variability, 56 consecutive type 2 diabetic patients in whom UTI was absent at the beginning of the study and during follow-up were included in the study as the control group. In total, four separate samples were collected from these patients at 3-month intervals, starting in January Diabetic patients with UTI Diabetic patients without UTI n Age (years) Sex (M/F) 3/56 25/31 Duration of diabetes (years) Creatinine ( mol/l) HbA 1c (%) AER ( g/min) 14 ( ) 13 (1 184) Normoalbuminuric patients (%) Microalbuminuric patients (%) Infecting organisms (%) Escherichia coli 67.8 Klebsiella pneumoniae 6.7 Streptococcus agalactiae 6.7 Enterococcus faecalis 6.7 Proteus mirabilis 5.0 Morganella morganii 3.4 Enterobacter cloace 1.7 Enterococcus durans 1.7 Data are means SD or median (range) unless otherwise noted. The biological within-subject variance (coefficient of biological variation; CVb) of AER was calculated in the four urine specimens collected at 3-month intervals according to the following formula: CVb (CVt 2 CVa 2 ) 1/2, where CVt is the total intra-individual coefficient of variation and CVa is the coefficient of analytical variation (8). To calculate CVt, it was assumed that values of the repeat measurements in the same subject (four in this case) were normally distributed. The formula used to calculate CVt was 100% SD/mean. Informed consent was obtained from all participants, and the study was approved by the hospital s human ethics committee. For statistical analysis, AER was logarithmically transformed to correct for skewed distribution; the results are expressed as medians and range. Withinpatient comparisons of AER in relation to UTI were carried out by paired Student s t test. Comparisons among categorical variables were done using the 2 test. All P values are based on a two-sided test of statistical significance. Significance was accepted at the level of P Statistical analyses were performed with the SSPS statistical package. RESULTS The frequency of UTI was higher in women than in men (56 of 431 [13%] vs. 3 of 334 [1%]; P 0.001). The main clinical features of the 59 diabetic patients in whom a UTI was diagnosed, as well as the microorganism causing the infection, are detailed in Table 1. After antimicrobial therapy, the UTI was eradicated in 46 of the 59 patients (78%). The AER did not significantly change after antimicrobial treatment in the whole group of patients with UTI (pre: 13.8 g/ min [ ] vs. post: 8.5 g/min [ ]; P 0.1). In addition, we did not observe any significant difference when the analysis was performed separately for patients in whom UTI was eradicated and those in whom UTI persisted after antimicrobial therapy. This was true for normoand microalbuminuric patients (Table 2). A decline in the median value was obtained in the group of microalbuminuric patients in whom UTI was eradicated. However, the differences were not statistically significant, and a similarly not significant decrease was observed in Table 2 AER outcome after antimicrobial therapy in patients in whom UTI was eradicated and in those in whom UTI was not eradicated n Before antimicrobial therapy After antimicrobial therapy UTI eradicated All patients ( ) 7.1 ( ) 0.14 Normoalbuminuric patients ( g/min) ( ) 5.2 (0.1 38) 0.34 Microalbuminuric patients ( g/min) (34 195) 45.8 (18 185) 0.12 UTI not eradicated All patients (2.9 70) 17 (1.7 80) 0.42 Normoalbuminuric patients ( g/min) (2.9 42) 13.3 (1.7 42) 0.84 Microalbuminuric patients ( g/min) ( ) 37.5 (19 80) 0.33 Data are median (range). P 1566 DIABETES CARE, VOLUME 27, NUMBER 7, JULY 2004

3 Hernández and Simó Figure 1 Measurements of AER performed before and after antimicrobial treatment in microalbuminuric patients in whom UTI was eradicated. The dashed line indicates the cut-off corresponding to an AER of 20 g/min. microalbuminuric patients in whom UTI was not eradicated. In addition, 3 of 10 microalbuminuric patients in whom UTI was eradicated showed an increase rather than a decrease in the AER after antimicrobial treatment. Furthermore, all but one patient remained in the microalbuminuric range after effective treatment of UTI (Fig. 1). In the single patient who became normoalbuminuric (18 g/min) after UTI treatment, only slight microalbuminuria (34 g/min) was detected before treatment. The results of AER measurements performed in the control group are shown in Table 3. The biological variation of AER was 64 27%. However, the CVb for AER varied widely among subjects (0 143%) and was inversely correlated with AER (r 0.44; P 0.001) (Fig. 2). Thus, the CVb of AER was higher in normo- than in microalbuminuric diabetic patients (72 24 vs %; P 0.01). The percentage of the reduction of AER in patients in whom UTI was solved (55 23%) did not exceed what would be expected by the biological variability of AER (64 27%). In addition, in the subset of patients with microalbuminuria in whom a decline in AER was detected after solving the UTI (n 7), the decrease did not exceed what would be expected by the biological variability of AER in microalbuminuric patients (49 20 vs ). The percentage of microalbuminuria misclassification was similar in the group with eradicated UTI and in the control group (6 of 46 [13%] vs. 9 of 56 [16%]; NS) (Fig. 2). It should be noted that the percentage of patients in whom AER was 20 g/min in the first determination and 20 g/min in the second analysis was similar in the group with eradicated UTI and in the control group (5 of 46 [11%] vs. 5 of 56 [9%]; NS) (Fig. 2). CONCLUSIONS Several factors have been considered as classical confounders when interpreting the results of AER (e.g., UTI, exercise, high-protein diet, acute hyperglycemia, hypertension, and AER variability). However, despite the widely recognized prognostic and therapeutic implications of microalbuminuria, some of these confounding factors are still controversial. For example, it has recently been reported that exercise does not increase AER in type 1 diabetic patients, as was previously assumed (9). In the present study, we provided evidence that the presence of asymptomatic or uncomplicated UTI does not significantly modify AER. Although it has been widely accepted that UTI can cause transient elevations in urinary albumin excretion (American Diabetes Association position statement), there are no consistent reports supporting this statement. In a cross-sectional study, Damsgaard and Mogensen (10) found that elderly type 2 diabetic women with UTI had an AER in the upper range, but that it was not significantly higher than it was in patients without UTI. Watts et al. (11) investigated the influence of UTI on AER in 20 type 1 diabetic patients and did not find significant changes in AER according to the presence or absence of UTI. In the present study, apart from including a large cohort of type 2 diabetic patients with UTI, the biological variability of AER was also determined in a group of diabetic patients without UTI. Our results showed that not only did UTI not influence AER, but also the changes in AER after antimicrobial treatment were similar in range to AER s biological variability. In addition, UTI did not significantly influence the classification of diabetic patients as normo- or microalbuminuric. The number of patients placed in the microalbuminuric group in whom UTI was eradicated was relatively small. Therefore, although the differences in AER before and after solving UTI were not statistically significant, further studies specifically focused on this group are needed. However, in practical terms, diabetic patients in whom microalbuminuria has been firmly established are not a problematic group when the possible false positive results of AER due to UTI are being analyzed. Instead, diabetic patients with normoalbu- Table 3 AER detected in the four measurements performed in the control group n First determination Second determination Third determination Fourth determination P Normoalbuminuric patients (1 30) 9 (2 49) 12 (1 36) 9 (1 38) NS Microalbuminuric patients (12 146) 28.5 (14 143) 32.5 (19 128) 25.5 (14 184) NS Data are median (range). Normoalbuminuria was defined as AER 20 g/min in at least three of the four determinations. Microalbuminuria was defined as an AER of g/min in at least two of the four determinations. DIABETES CARE, VOLUME 27, NUMBER 7, JULY

4 Urinary infection and albumin excretion rate Figure 2 Correlation between baseline AER and its CVb. As can be observed, CVb was inversely correlated with AER, and, therefore, there was more variation with low levels of AER. The dashed line indicates the cut-off corresponding to AER of 20 g/min. minuria represent the potential group at risk for false positive results (from normoto microalbuminuria) due to UTI. Overall, our data do not support the concept that UTI has to be ruled out when assessing AER. It is noteworthy that this approach, apart from simplifying the management of diabetic patients, would also save resources invested in patient care. It could be argued that if patients are not screened for UTI, the disease cannot be diagnosed. However, it should be noted that it has been recently established that diabetes itself should not be an indication for screening for or treatment of asymptomatic bacteriuria (12). There is a considerable intraindividual variability in AERs; the CVb previously reported ranged between 25 and 62% (13 16). In the present study, we confirmed the high intra-individual biological variation of AER (64%), thus supporting the view that it is necessary to consider this confounding factor when evaluating changes of AER after clinical intervention. The high variability obtained could be explained by the duration of the study, which was longer than that of other studies previously reported. The use of 24-h albumin excretion samples could be another reason accounting for the high AER variability. Some authors consider that it is better to use the albumin/creatinine ratio because it may correct for errors in the collection of timed urine samples (17). However, other authors consider that the introduction of another biological variable (urinary creatinine) is unlikely to reduce AER variability. In this regard, Watts et al. (18) reported that the variability was comparable for urine albumin concentration, the albumin/creatinine ratio, and AER. In the present study, we found that the variability of AER was inversely related to its magnitude. Mosca et al. (16) also reported a higher biological variability of AER in normo- than in microalbuminuric type 2 diabetic patients, although other authors did not find this negative association (5). As expected, we observed a higher percentage of UTI in women than in men (13 vs. 0.9%). The prevalence of UTI observed in the type 2 diabetic women was within the range previously reported (7.9 26%) (6,18 20). The prevalence of infecting microorganisms in the present study was also the same as that previously reported in diabetic patients (6,12,21), with Escherichia coli being the most frequent. In summary, the presence of asymptomatic UTI does not significantly influence the measurement of AER, and, therefore, testing for UTI could be avoided when screening for microalbuminuria in diabetic patients. Acknowledgments This study was supported by grants from Novo Nordisk Pharma S.A. (01/0066) and the Instituto de Salud Carlos III (G03/212 and C03/08). We thank Carme Creus and Dr. Carme Ricós for technical assistance. References 1. American Diabetes Association: Diabetic nephropathy (Position Statement). Diabetes Care 27 (Suppl. 1):S79 S83, Mogensen CE: Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 310: , Jarrett RJ, Viberti GC, Agryopropoulos A, Hill RD, Mahmud U, Murrells TJ: Microalbuminuria predicts mortality in noninsulin dependent diabetics. Diabet Med 1:17 19, Stehouwer CDA, Nanta JJP, Zeldenrunt GC, Hackeng WHL, Donker AJM, den Ottolander GJH: Urinary albumin excretion, cardiovascular disease and endothelial dysfunction in non-insulin dependent 1568 DIABETES CARE, VOLUME 27, NUMBER 7, JULY 2004

5 Hernández and Simó diabetes mellitus. Lancet 340: , Mogensen CE, Vestbo E, Poulsen PL, Christiansen C, Damsgaard EM, Eiskjaer H, Froland A, Hansen KW, Nielsen S, Pedersen MM: Microalbuminuria and potential confounders: a review and some observations on variability of urinary albumin excretion. Diabetes Care 18: , Geerlings S, Stolk RP, Camps MJL, Netten PM, Hoekstra JBL, Bouter KP, Bravenboer B, Collet JT, Jansz AR, Hoepelman AIM, for the Diabetes Mellitus Women Asymptomatic Bacteriuria Utrecht Study Group: Asymptomatic bacteriuria may be considered a complication in women with diabetes. Diabetes Care 23: , Boyko E, Fihn S, Scholes D, Chen C, Normand E, Yarbro P: Diabetes and the risk of acute urinary tract infection among postmenopausal women. Diabetes Care 25: , Fraser CG, Harris EK: Generation and application of data on biological variation in clinical chemistry. Crit Rev Clin Lab Sci 27: , Lane JT, Ford TC, Larson LR, Chambers WA, Lane PH: Acute effects of different intensities of exercise in normoalbuminuric/normotensive patients with type 1 diabetes. Diabetes Care 27:28 32, Damsgaard EM, Mogensen CE: Microalbuminuria in elderly hyperglycaemic patients and controls. Diabet Med 3: , Watts GF, O Brien SF, Shaw KM: Urinary infection and albumin excretion in insulin-dependent diabetes mellitus: implications for the measurement of microalbuminuria. Diabet Med 13: , Harding GK, Zhanel GG, Nicolle LE, Cheang M, Manitoba Diabetes Urinary Tract Infection Study Group: Antimicrobial treatment in diabetic women with asymptomatic bacteriuria. N Engl J Med 347: , Cohen DL, Close CF, Viberti GC: The variability of overnight urinary albumin excretion in insulin-dependent diabetic and normal subjects. Diabet Med 4: , Dullaart RP, Roelse H, Sluiter WJ, Doorenbos H: Variability of albumin excretion in diabetes. Neth J Med 34: , Eshoj O, Feldt-Rasmussen B, Larsen ML, Mogensen EF: Comparison of overnight, morning and 24-hour urine collections in the assessment of diabetic microalbuminuria. Diabet Med 4: , Mosca A, Paleari R, Ceriotti F, Lapolla A, Fedele D, Lercanidipine Study Group: Biological variability of albumin excretion rate and albumin-to-creatinine ratio in hypertensive type 2 diabetic patients. Clin Chem Lab Med 2003;41: Smulders YM, Slaats EH, Rakic M, Smulders FT, Stehouwer CD, Silberbusch J: Short-term variability and sampling distribution of various parameters of urinary albumin excretion in patients with noninsulin-dependent diabetes mellitus. J Lab Clin Med 132:39 46, Watts GF, Morris RW, Khan K, Polak A: Urinary albumin excretion in healthy adult subjects: reference values and some factors affecting their interpretation. Clin Chim Acta 172: , Schmitt JK, Fawcett CJ, Gullickson G: Asymptomatic bacteriuria and HbA1c. Diabetes Care 9: , Zhanel GG, Nicolle LE, Harding GK: Prevalence of asymptomatic bacteriuria and associated host factors in women with diabetes mellitus: the Manitoba Diabetic Urinary Infection Study Group. Clin Infect Dis 21: , Goswami R, Bal CS, Tejaswi S, Punjabi GV, Kapil A, Kochupillai N: Prevalence of urinary tract infection and renal scars in patients with diabetes mellitus. Diabetes Res Clin Pract 53: , 2001 DIABETES CARE, VOLUME 27, NUMBER 7, JULY