PEDIATRICS Vol. 124 No. 1 July 2009, pp. 23-29 (doi:10.1542/peds.2008-1192)
ARTICLE |
Age-Related Renal Parenchymal Lesions in Children With First Febrile Urinary Tract Infections
a Department of Pediatrics, DPMSC
b Institute of Hygiene and Epidemiology, University of Udine, School of Medicine, Udine, Italy
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE: The aim of this study was to define the association between age and the occurrence of acute pyelonephritis and renal scars.
METHODS: Between 1999 and 2002, all children 0 to 14 years of age consecutively seen with a first febrile urinary tract infection were enrolled in the study. 99mTc-Dimercaptosuccinic acid renal scintigraphy was performed within 5 days after admission for the detection of renal parenchymal involvement. The presence of vesicoureteral reflux was assessed by using cystography performed 1 month after the infection. If the acute scan results were abnormal, then follow-up 99mTc-dimercaptosuccinic acid scanning was performed after 6 months, to assess the frequency of scars.
RESULTS: A total of 316 children were enrolled in the study (190 children <1 year, 99 children 1–4 years, and 27 children 5–14 years of age). 99mTc-Dimercaptosuccinic acid scintigraphy revealed that 59% of the children had renal involvement in the acute phase of infection. The frequency of kidney involvement in infants <1 year of age (49%) was significantly lower than that in children 1 to 4 years of age (73%) and >5 years of age (81%). Of the 187 children with positive acute 99mTc-dimercaptosuccinic acid scan results, 123 underwent repeat scintigraphy after 6 months. Renal scars were found for 28% of children <1 year, 37% of children 1 to 4 years, and 53% of children 5 to 14 years of age. No significant differences in the frequency of scars and the presence or absence of vesicoureteral reflux were noted.
CONCLUSIONS: Our findings confirm that acute pyelonephritis and subsequent renal scarring occur only in some children with first febrile urinary tract infections. Children <1 year of age with febrile urinary tract infections have a lower risk of parenchymal localization of infection and renal scarring.
Key Words: acute pyelonephritis • children • vesicoureteral reflux • renal scarring
Abbreviations: UTI—urinary tract infection • APN—acute pyelonephritis • DMSA—99mTc-dimercaptosuccinic acid • SPECT—single photon emission computed tomography • VUR—vesicoureteral reflux • ESR—erythrocyte sedimentation rate • CRP—C-reactive protein • WBC—white blood cell • TLR4—Toll-like receptor 4 • OR—odds ratio • CI—confidence interval
Febrile urinary tract infection (UTI) is one of the most frequent pediatric disorders.1 Despite its common occurrence, diagnostic evaluation and management remain a challenge for pediatricians, because localization of UTIs in children is sometimes difficult. Clinical parameters such as fever and flank pain and laboratory markers such as erythrocyte sedimentation rate (ESR) values, C-reactive protein (CRP) levels, and white blood cell (WBC) counts are nonspecific and cannot differentiate acute pyelonephritis (APN) from UTI without renal involvement, especially in young children.2 This distinction is important, because APN is associated with irreversible parenchymal damage (scarring) and eventual development of hypertension and chronic renal failure3; therefore, optimal management of UTI necessitates early detection of parenchymal renal infection. At present, 99mTc-dimercaptosuccinic acid (DMSA) renal scintigraphy is considered the standard method for diagnosis of APN and for assessment of the extent and progression of renal parenchymal damage.4–6
Many studies have shown that susceptibility to the kidney-damaging effects of UTIs decreases with age. In particular, children <1 year of age have been reported to have a greater risk of renal sequelae.7–10 These findings have led to different approaches for the evaluation and treatment of children with first febrile UTIs according to age, with more-aggressive evaluation for those <1 year of age, compared with older children (in particular, >5 years of age). The aim of this prospective study was to evaluate the association between age and the clinical and biological characteristics of children with first febrile UTIs who develop pyelonephritis and renal scars.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Study Design
All children with a first febrile UTI who were admitted to the Department of Pediatrics of the University of Udine (Udine, Italy) between January 1999 and December 2002 were included in this prospective study. Children were seen directly in our clinic or were referred to the investigators by family pediatricians, who usually collaborate in the treatment of all patients with febrile UTIs. This study design reflects the standard approach to UTIs we use in our department, in which parents are always informed of the nature, aims, and potential risks and benefits of DMSA scintigraphy and cystourethrography. Patients with a history of previous febrile UTIs or with known urinary tract anomalies were excluded.
Febrile UTI was defined as positive urine culture results (single microorganism with a colony count of 
105 colony-forming units per mL) for a febrile child (temperature: 38°C) presenting without signs other than abdominal/flank pain and, for children <1 year of age, irritability, vomiting, feeding problems, or failure to gain weight. Urine samples were collected through clean voiding or bladder catheterization.
All patients were treated initially with intravenous antibiotic (ceftriaxone) therapy for 1 to 5 days, followed by oral treatment chosen on the basis of antibiotic sensitivity testing. The overall duration of antibiotic treatment was 10 days.
DMSA renal single photon emission computed tomography (SPECT) was performed within the first 5 days after the diagnosis of UTI, to detect acute renal parenchymal involvement. Cystourethrography was performed after 1 month, for detection and grading of vesicoureteral reflux (VUR), for children whose parents gave their consent (90%). Two thirds of children with positive first DMSA scan results underwent follow-up scanning 6 months after the initial scanning, to identify permanent renal damage (scar). Follow-up DMSA scanning was not performed for children whose parents denied consent or for those found to have minor or no abnormalities in the first DMSA scan. Furthermore, children with positive initial scan results were not restudied if a UTI occurred during the 6-month interval. The age distribution of children who did not undergo follow-up scanning was similar to that of children who did undergo follow-up scanning. All examined children had totally or partially reversible renal lesions on late DMSA scans, which confirmed retrospectively the diagnosis of APN and excluded preexisting scars.
Clinical and Laboratory Assessments
Clinical data recorded included body temperature and days of fever before the diagnosis of UTI. Laboratory assessments were performed at admission and included WBC count, ESR, and CRP level measurements, urinalysis, and urine culture.
Imaging Studies
Children underwent DMSA renal SPECT within 5 days after admission and underwent follow-up scanning after 6 months if the first scan results indicated an acute renal lesion. The patients were given injections of 0.750 to 1.5 mCi of DMSA (dose calculated according to body weight), and SPECT was performed after 2 to 3 hours. Images were acquired by using a triple-headed camera (Siemens, Siemans, Germany), with low-energy, high-resolution collimators. Images were obtained in a 360° noncircular orbit (body contour). A total of 120 projection images were acquired (40 for each detector) on a 128 x 128 matrix, with 1.45x zoom (pixel size: 5.2 mm). Patient motion was evaluated by viewing cine images. The data were reconstructed through filtered back-projection by using a Butterworth filter with a cutoff value of 0.45 cycles/cm and order of 7 kHz. No attenuation corrections were made.
A scan was considered to be positive for an acute renal lesion when it showed focal, multifocal, or diffuse areas of decreased DMSA uptake in the kidney without volume loss. Renal scar was diagnosed when 1 area of focal decreased uptake was noted in association with contraction and loss of volume in the involved renal cortex. Each lesion present in the late scan was compared with findings in the early scan through topographic analysis.
Cystourethrography for VUR detection and grading was performed 1 month after acute infection. The cystograms were obtained with standard radiographic techniques (voiding cystourethrography with iodinated contrast material) for boys and through radionuclide cystography (direct radionuclide cystography with 99mTc) for girls. Voiding cystourethrography was preferred for boys because this technique allowed evaluation of the urethra to exclude posterior urethral valves. The radiographic cystograms were evaluated for the presence and grade of VUR by using the international grading system. DMSA scintigrams and cystograms were each read by a single radiologist, to reduce interobserver variability.
Statistical Analyses
Frequency distributions for study participants were calculated according to patients' clinical (age, gender, days of fever before diagnosis, and mean daily body temperatures) and laboratory (ESR, CRP level, VUR, and WBC count) characteristics The associations between age and other variables were evaluated by means of 
2 tests.
The associations between positive DMSA scan results during the acute phase of UTI and each of the other variables first were evaluated by using univariate logistic regression analysis and measured with crude odds ratios (ORs). The statistical significance of these associations is indicated by 95% confidence intervals (CIs) and P values.
Subsequently, multivariate logistic regression analysis was performed to control for the potential confounding effects of each variable on the associations between positive acute DMSA scan results and the other factors. The multivariate model included terms for age, gender, ESR, CRP level, VUR, WBC count, duration of fever before diagnosis, and mean daily temperature. Adjusted ORs, 95% CIs, and P values are presented only for variables that were significantly associated with positive acute DMSA scan results. The existence of a linear trend in the association between age and positive DMSA scan results was assessed by using age as a continuous variable in the multivariate logistic regression model; the P value for the test for trend is presented.
Finally, among children with positive DMSA scan results in the acute phase of UTI, the risk of positive follow-up DMSA scan results after 6 months was evaluated according to age group and the presence of VUR. A logistic regression model was used, with age and VUR as independent variables because they were the 2 principal factors of interest. Results from this model are expressed as ORs, 95% CIs, and P values. A test for linear trend for age was performed by including age in the model as a continuous variable.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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A total of 316 children (223 girls and 93 boys), 1 month to 14 years of age (median age: 1.6 years), were enrolled in the study. Of these children, 190 (60%) were <1 year of age, 99 (31%) were 1 to 4 years of age, and 27 (9%) were 5 to 14 years of age.
Table 1 presents selected characteristics of the children according to age. There were no significant differences among the 3 age groups with respect to ESR, duration of fever before the diagnosis of UTI, or frequency of VUR. The female/male ratio was slightly in favor of girls for patients <1 year of age and increased strongly for older children. The proportions of children with CRP levels of 102 mg/L and with maximal temperatures of >39.5°C were greater for children 1 year of age, compared with younger children.
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Of the 316 children included, 187 (59%) showed positive renal DMSA scan results in the acute phase of the infection. Table 2 shows the univariate relationships between the acute DMSA scan results and selected characteristics of the children. The odds of positive scan results increased significantly with age; the odds of positive scan results were almost 3 times greater for children 1 to 4 years of age than for children <1 year of age and were
4.5 times greater for children 5 years of age than for children <1 year of age. An increased risk of positive scan results was found for children with ESR values of 68 mm/hour, compared with children with ESR values of <45 mm/hour. The risk of positive scan results increased significantly as CRP levels increased. Children with WBC counts of >15000 cells per µL were 1.8 times more likely to have positive scan results than were those with WBC counts of <11000 cells per µL. Children who had fever for 2 days before diagnosis had a 25% increased risk of positive scan results. Children with maximal temperatures of >38.5°C had an increased risk of positive scan results, compared with children with maximal temperatures of <38°C. A positive association was observed between positive acute DMSA scan results and the presence of VUR (OR: 2.02).
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The independent associations between age, CRP level, WBC count, and VUR and positive acute DMSA scan results were confirmed in a multivariate regression analysis (Table 3). Children 5 to 14 years of age seemed to have substantially greater odds of positive scan results than did children <1 year of age, after controlling for other factors. In addition, the risk of positive scan results seemed to increase linearly with age (P = .0033).
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Of the 187 children with positive acute DMSA scan results, 123 underwent scintigraphy after 6 months. Eighty (65%) showed complete normalization of renal lesions and 43 (35%) showed scars (Table 4). After adjustment for the presence of VUR, children
5 years of age had a significant threefold increase in the odds of positive follow-up scan results, compared with children <1 year of age. The excess risk for children 1 to 4 years of age was not statistically significant. A linear trend for age was noted (P = .0598). In contrast, after controlling for age, the presence of VUR was not significantly associated with renal scarring.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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With febrile UTIs, a major concern is the identification of patients at risk for permanent renal damage. With the availability of renal scintigraphy, many studies have shown that not all children with febrile UTIs have parenchymal localization of the infection.5,6
Our study was conducted with 316 children <14 years of age with a first occurrence of febrile UTI. In our area, all family pediatricians collaborate with our team and usually refer all patients with febrile UTIs to our clinic for evaluation, imaging, and treatment. Therefore, we consider our study population to represent an unbiased sample of children with febrile UTIs. Because we focused on renal localization, we excluded children with previous UTIs and children with known urinary tract malformations, which often are associated with renal dysplasia. All patients with previous episodes of confirmed or probable UTI were excluded. Moreover, all acute renal lesions showed total or partial regression in the follow-up DMSA scans, which confirms the diagnosis of APN.
To date, DMSA scintigraphy is considered the standard imaging technique for the detection and evaluation of APN and renal scarring in children.4 At the time of acute infection, the area of low uptake of the tracer reflects the extent of inflammation and ischemia. It is estimated that 60% of patients with a febrile UTI have APN5,11–13; in our population, 59% of children presented APN documented with DMSA scans, which confirms that not all children with febrile UTIs have parenchymal localization of the infection.
In clinical practice, acute-phase reactants (ESR, CRP level, and WBC count) are commonly used in the attempt to differentiate between upper and lower UTIs. CRP levels have been shown to have good sensitivity but low specificity for the diagnosis of parenchymal infection.2,5 Recently, procalcitonin, a new marker for infection, has been shown to be better in discriminating febrile UTIs with renal involvement from those without such involvement and in predicting subsequent scars.14
In our study, CRP levels, among biological parameters, best correlated with renal involvement in the acute phase of UTI. Although mean CRP levels were higher for patients with renal localization of infection, there was a wide overlap of values between children with pathologic and normal DMSA scans, which confirms the low specificity of this parameter. All DMSA scans were pathologic only in the group of patients with CRP levels of >200 mg/L (data not shown).
Many studies have clearly demonstrated that VUR is not a prerequisite for renal involvement among children with febrile UTIs and that renal scarring can be observed even without VUR.5,8,12,13,15,16 In our study, although the presence of VUR was associated with increased risk of renal lesions in the acute phase of UTI (OR: 2.02; P = .02), 61% of children with positive early DMSA scan results had no VUR. The results confirm that a large proportion of febrile UTIs, as documented with acute DMSA scans, occur in the absence of VUR. In identifying renal involvement during febrile UTIs, fever showed a correlation with APN; in particular, high-grade fever (39.5°C) was revealed to be the best marker of APN (OR: 14.17; P = .01).
The renal damage from the initial insult of APN leads to the development of an irreversible renal scar in 40% to 60% of affected children.17–19 In our study population, the incidence of renal scars was 35%. This may be underestimated, because not all children underwent repeat DMSA scanning. In our experience, parents of children with important lesions on DMSA scans during febrile UTIs rarely refuse consent for repeat renal scanning for detection of scarring. It is likely that we missed only patients with minor lesions on acute scans that probably would not show a scar on the follow-up DMSA scans.
Infants <12 months of age have been considered to have a greater risk for acute renal damage and subsequent renal scarring, relative to older children.7–10 This view has led to more-aggressive treatment and a different imaging approach for infants with UTIs; this opinion probably was based on the fact that previous studies included very young children, mostly boys, with severe VUR and congenital renal dysplasia.
The belief that age of <1 year is a risk factor for renal damage has been challenged by some studies. Benador et al20 investigated the incidence of renal lesions in children 0 to 16 years of age and showed that risk for acute and permanent renal damage secondary to UTI did not decrease with age. Lin et al21 reported a higher incidence of APN in older children (1–17 years of age), whereas renal scarring was equally prevalent in different age groups. Similarly, Ataei et al22 found acute inflammatory changes on DMSA scans for 78.8% of children >5 years of age who were admitted with a first symptomatic UTI. The authors hypothesized that this finding might have been attributable to the different criteria used for admission for infants and older children.
In our study, children >5 years of age had a higher risk of APN than did children <12 months of age (adjusted OR: 11.26; P = .002). Moreover, we found that the risk of renal scarring was indeed increased in older children (OR: 3.35; P = .04), with a positive correlation between age and risk of renal lesions. In a multivariate analysis controlling for age, the presence of VUR was not associated with renal scarring. It is worth noting than our population had similar characteristics with respect to the incidence of VUR and the duration of fever before diagnosis, which excludes 2 important potential selection biases (Table 1). It is unlikely that the risk of renal involvement in older children was attributable to delays in diagnosis and treatment.
The prognostic importance of renal parenchymal involvement in febrile UTI has been highlighted. Only children with parenchymal lesions in the acute phase are likely to develop scars and associated complications.3 Therefore, the observation of the lower incidence of parenchymal involvement in the acute phase of UTI in small children seems very relevant. Experimental data from laboratory animals showed that the inflammatory reaction to bacterial infection plays an important role in the pathogenesis of renal lesions.23 In our study, acute-phase inflammatory parameter values were higher in older children and were correlated with renal involvement. During UTIs, the minor inflammatory reaction that occurs in infants might be protective with respect to acute and permanent renal damage. In the first step of a UTI, uropathogens are recognized by epithelial Toll-like receptor 4 (TLR4) through mechanisms involving specific virulence factors. The activated epithelial cells respond to local infection with the release of multiple cytokines, chemokines, and other factors that orchestrate the cellular constituents of the innate immune response.24 Recently, Ragnarsdóttir et al25 demonstrated reduced TLR4 expression in children who developed asymptomatic bacteriuria rather than symptomatic disease. Moreover, in patients with febrile UTIs, TLR4 expression was found to be increased in relation to the presence of renal scarring on follow-up DMSA scans. On the basis of these results, it might be speculated that infants have a certain degree of immaturity of the innate immune response and of TLR4 signaling, which is essential for mucosal defense. As a result, infants might have incomplete activation of the inflammatory cascade, which would protect them from acute and permanent renal damage. This observation needs to be confirmed in further studies.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Although not all febrile UTIs show parenchymal localization on acute DMSA scans (APN), a significant proportion of children with positive DMSA scan results for a first APN episode might develop renal scars. Commonly used acute-phase reactant tests are not specific in detecting renal involvement, elevated temperatures represent the best clinical marker of APN, and the presence of VUR does not identify a population at risk for APN and renal scarring. Moreover, we confirm that infants with febrile UTIs have a lower risk of renal parenchymal localization of infection and renal scarring, compared with children 1 to 14 years of age.
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FOOTNOTES |
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Accepted Nov 14, 2008.
Address correspondence to Enrico Vidal, MD, Department of Pediatrics, Azienda Ospedaliero-Universitaria di Udine, P.le S. Maria della Misericordia, 15, 33100 Udine, Italy. E-mail: enrico.vidal{at}inwind.it
Financial Disclosure: The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject: The epidemiological features and risk factors of febrile UTIs have been studied, but few authors have pointed to the relationship between age and kidney involvement. Children <1 year of age are considered to have a higher risk of renal sequelae.
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| What This Study Adds: A positive correlation between age and renal involvement in children with first febrile UTIs was identified. Children <1 year of age with febrile UTIs had a lower risk of parenchymal localization of infection and renal scarring.
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PEDIATRICS (ISSN 1098-4275). ©2009 by the American Academy of Pediatrics
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