PEDIATRICS Vol. 122 No. 3 September 2008, pp. 486-490 (doi:10.1542/peds.2007-2894)
ARTICLE |
Early Treatment of Acute Pyelonephritis in Children Fails to Reduce Renal Scarring: Data From the Italian Renal Infection Study Trials
a Department of Pediatric Nephrology, Princess Margaret Hospital, Perth, Australia; Departments of
b Nuclear Medicine
f Pediatric Nephrology, Azienda Ospedaliera-University of Padua, Padua, Italy
c Pediatric Unit, Camposampiero Hospital, Padua, Italy
d Pediatric Unit, Mestre Hospital, Mestre, Italy
e Pediatric Unit, Bologna General Hospital, Bologna, Italy
g Pediatric Unit, Motta di Livenza Hospital, Livenza, Italy
h Pediatric Unit, Castelfranco Hospital, Castelfranco, Italy
i Pediatric Unit, Chioggia Hospital, Chioggia, Italy
j Pediatric Unit, Arzignano Hospital, Arzignano, Italy
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVES. The American Academy of Pediatrics recommendation for febrile infants and young children suspected of having a urinary tract infection is early antibiotic treatment, given parenterally if necessary. In support of this recommendation, data suggesting that delay in treatment of acute pyelonephritis increases the risk of kidney damage are cited. Because the risk was not well defined, we investigated renal scarring associated with delayed versus early treatment of acute pyelonephritis in children.
METHODS. The research findings are derived from 2 multicenter, prospective, randomized, controlled studies, Italian Renal Infection Study 1 and 2, whose primary outcomes dealt with initial antibiotic treatment and subsequent prophylaxis, respectively. From the 2 studies, we selected the 287 children with confirmed pyelonephritis on acute technetium-99m-dimercaptosuccinic acid scans who underwent repeat scanning to detect scarring 12 months later. The children were 1 month to <7 years of age when they presented with their first recognized episode of acute pyelonephritis in northeast Italy.
RESULTS. Progressive delay in antibiotic treatment of acute pyelonephritis from <1 to 
5 days after the onset of fever was not associated with any significant increase in the risk of scarring on technetium-99m-dimercaptosuccinic acid scans obtained 1 year later. The risk of scarring remained relatively constant at 30.7 ± 7%. Clinical and laboratory indices of inflammation were comparable in all groups, as was the incidence of vesicoureteric reflux.
CONCLUSIONS. Early treatment of acute pyelonephritis in infants and young children had no significant effect on the incidence of subsequent renal scarring. Furthermore, there was no significant difference in the rate of scarring after acute pyelonephritis when infants and young children were compared with older children.
Key Words: urinary tract infection • renal scar • technetium-99m-dimercaptosuccinic acid scan • antibiotic treatment
Abbreviations: IRIS—Italian Renal Infection Study • DMSA—technetium-99m-dimercaptosuccinic acid • UTI—urinary tract infection
Renal scarring is a frequent outcome of acute pyelonephritis in children,1–3 with urinary tract infection (UTI) now being considered the most common, serious, bacterial infection that occurs in infancy and early childhood in the developed world.4 The adverse long-term effects of UTI, such as hypertension, proteinuria, and the possibility of chronic renal failure, are secondary to the presence of scarring.5 The American Academy of Pediatrics identified the population at greatest risk of incurring renal damage from UTI as being infants and young children with UTI and fever.6 In its primary recommendation, it expressed concern regarding any delay in the diagnosis and treatment of febrile UTI, citing clinical and experimental data supporting the concept that a delay in the treatment of acute pyelonephritis increases the risk of kidney damage.7,8 Both cited studies included small numbers of children, were retrospective, and had severe limitations. In the first study,7 no statistical analysis was performed to support the authors' assertions. The second article8 provided no information on patient selection, and the diagnosis of pyelonephritis was poorly defined. This is the first study to examine in a detailed manner the issue of delayed treatment of acute pyelonephritis as a risk factor for latter scarring, with a large cohort of children presenting with their first recognized episode of acute pyelonephritis.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Study Group
As part of 2 controlled, randomized, multicenter, open-label, parallel-group trials with children presenting with their first documented episode of acute pyelonephritis in northeast Italy, that is, Italian Renal Infection Study (IRIS) 1 and 2, we identified 287 children. IRIS 1 dealt with antibiotic treatment of the initial infection, and children were assigned randomly to receive orally administered co-amoxiclav (50 mg/kg per day, in 3 divided doses, for 10 days) or parenterally administered ceftriaxone (50 mg/kg per day, in a single dose, for 3 days) followed by orally administered co-amoxiclav (50 mg/kg per day, in 3 divided doses, for 7 days).9 This study took place between June 2000 and July 2005. IRIS 2 was a trial of antibiotic prophylaxis versus no treatment in the follow-up period that was completed in August 2006.10 All patients were reevaluated according to protocol at 72 hours after commencement of antibiotic treatment, with urine microscopy and culture, full blood counts, and measurements of indices of inflammation. Both study protocols were approved by the ethics committees of each of the 28 participating centers. Written informed consent was obtained from the parents of all participants.
Children recruited to IRIS 1 and 2 were 1 month to <7 years of age at the time of their first recognized episode of acute pyelonephritis. The diagnosis was based on a confirmed UTI, with a white blood cell count of 25 cells per µL (1+ with a dipstick) and growth of a single microorganism at 100000 colony-forming units per mL in 2 consecutive tests, as well as 2 of the following criteria: fever of 38°C (in the first 6 months of life, fever was not an essential criterion), inflammation indices in the first 48 hours (erythrocyte sedimentation rate of 30 mm/hour and/or C-reactive protein level 3 times the upper limit of the reference range), or neutrophil levels above normal values for age.11 Although all children recruited to IRIS 1 and 2 were considered for inclusion, this analysis was restricted to children from the 2 studies with acute, positive, technetium-99m-dimercaptosuccinic acid (DMSA) scans performed within 10 days after the commencement of antibiotic treatment, with follow-up scans completed 12 months later. DMSA scanning is considered the standard method for the diagnosis of acute pyelonephritis and renal scars.12 In addition, normal prenatal ultrasound results were required for all children. Exclusion criteria included creatinine clearance of 
70 mL/minute per 1.73 m2 (with the formula described by Schwartz et al13), documented renal and/or urologic abnormalities, and any previous antibiotic administration for that episode of infection.
Procedures and Scintigraphy
A detailed history was obtained from the parents according to protocol, and the duration of fever before admission was documented. After urine specimens were obtained, the children were treated with antibiotics. Acute DMSA scans were obtained to confirm acute pyelonephritis, with scanning 12 months later to assess the presence or absence of scarring at the site of previously documented infection.
Static renal scintigraphy was performed as described previously.14 Focal or diffuse areas of decreased uptake in the first scan, without evidence of cortical loss, were considered indicative of acute pyelonephritis. Renal scarring on the second scan was defined as decreased uptake with distortion of the contours or cortical thinning with loss of parenchymal volume in the region of the previous acute pyelonephritis. Two nuclear medicine physicians who were blinded to the patients' test results interpreted the scans independently. Discrepancies, which occurred in 10.5% of cases, were resolved through discussion between the evaluators.
Statistical Analyses
All statistical calculations were performed with Stata 8.1 (Stata, Chicago, IL). Results are reported as means ± SD for continuous variables and as proportions for categorical variables. Differences between groups for continuous variables were analyzed with Student's t test and 1-way analysis of variance; categorical variables were analyzed with Pearson's 
2 test or Fisher's exact test. Because the data were derived from 2 multicenter, prospective, controlled studies, statistical analyses proceeded as follows. Univariate analyses were performed for all single variables considered in the study. The data were then stratified according to duration of fever (in days) before treatment, to assess the homogeneity of the stratification. Bivariate analyses were performed to assess the relationships of the independent variables (among which the principal variable was the duration of fever), with the dependent variable being evidence of scarring on the 12-month DMSA scan. Correlation coefficients were calculated for all measured variables, for evidence of colinearity. Finally, logistic regression models were used to calculate odds ratios, with particular interest in the variables that were affected by the duration of fever before antibiotic treatment. All P values were 2-sided.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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A total of 298 children were identified according to our selection criteria. Subsequent exclusions included 5 patients for whom there was uncertainty regarding the exact duration of fever before commencement of therapy and 6 patients who were deemed to have a new scar not at the site of the original pyelonephritis. This left 287 children (198 girls and 89 boys; mean age: 15 months) who fulfilled all criteria and were included in the analysis. Treatment of the acute infection was as follows: oral co-amoxiclav therapy for 10 days for 149 children and initial parenteral ceftriaxone treatment for 3 days, followed by oral co-amoxiclav therapy for 7 days, for 138 children. Escherichia coli was the pathogen responsible in >90% of the urine cultures. Urine sterilization rates were comparable between the 2 treatment groups (99%), as were antibiotic resistance rates.
When all children were assessed for the presence of scarring on DMSA scans at the site of pyelonephritis documented in the acute study, there was no significant difference in the incidence of scarring with progressive delay in the initiation of antibiotic therapy from <1 to 5 days after the onset of fever (rate of scarring: 30.7 ± 7.0%; odds ratio: 0.99; 95% confidence interval: 0.65–1.51; P = .97) (Table 1). When analysis was restricted to the 227 children who were 1 month to 2 years of age at the time of pyelonephritis, similar results were obtained (rate of scarring: 30.4 ± 4.9%; odds ratio: 1.35; 95% confidence interval: 0.62–2.94; P = .45). Finally, we divided the children into 4 age quartiles for the first 2 years and a fifth group between 2 and <7 years of age, with no pattern of increased scarring appearing in a statistical analysis in relation to age (P = .19) (Table 2).
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When results were evaluated for severity of illness by using indices of inflammation, levels of fever at admission were similar for all groups, as were total white blood cell counts (Table 3). There was a modest reduction in the neutrophil count for patients who had a fever for
4 days before therapy, which did not reach significance (P = .08). The C-reactive protein level was consistently elevated and showed no significant difference with a delay in treatment, whereas the erythrocyte sedimentation rate demonstrated a significant increase with increasing duration of illness (P = .02). The failure of early antibiotic treatment to reduce subsequent scarring significantly was seen despite the effectiveness of antibiotics in causing resolution of fever a mean of 1.6 ± 0.1 days after administration (Table 1).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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There is an almost universally held view in the literature and publicized evidence-based clinical guidelines that early aggressive therapy of acute pyelonephritis in children, particularly very young children, is essential to reduce the subsequent frequency and degree of scarring.15–20 The most recent clinical practice guidelines of the American Academy of Pediatrics6 recommend the early administration of antibiotics, either orally or intravenously, for infants and young children with suspected or proven UTIs or pyelonephritis. As evidence in support of this, 2 articles are cited, in which "clinical and experimental data support the concept that delay in instituting appropriate treatment of acute pyelonephritis increases the risk of kidney damage."
Both articles report retrospective chart reviews with limited patient numbers. The first7 identified 37 children over a 15-year period who were deemed to have acquired scars after either pyelonephritis or pyrexia of unknown origin. Insufficient detail was provided and no statistical analysis was performed to support the authors' assertion that "episodes of acute pyelonephritis should be treated early and aggressively to prevent renal scarring."7 The second article8 described 52 children, 1 to 12 years of age (with no information on patient selection), for whom attempts were made in discussions of the symptoms with parents to determine when UTIs first commenced, with the diagnosis of acute pyelonephritis being poorly defined. More recently, Hoberman et al,21 in a large prospective study of oral versus intravenous therapy for UTIs in young febrile children, reported a slightly higher but not significantly different incidence of scarring among children who presented for care after 24 hours of fever, compared with those who presented sooner. Those authors noted that their findings were "consistent with the prevailing opinion that scarring is more common when there is either a delay in initiating treatment or when there is a sluggish response to therapy."21 Additional reasons for the ready acceptance of the idea that early antibiotic treatment reduces subsequent scarring, in the absence of good scientific evidence, stem from several sources, including the effectiveness of antibiotics in promoting rapid clinical recovery, laboratory data that demonstrate early reductions in inflammatory cytokine levels,22,23 and limited animal studies indicating that antibiotic treatment <24 hours after direct infection of the kidney can prevent significant inflammation and subsequent scarring.24,25
Our study, involving large numbers of patients, is the first to undertake a detailed examination of whether delay in instituting appropriate treatment of acute pyelonephritis increases the risk of kidney damage. When cases were stratified according to the duration of clinical pyelonephritis (determined as the duration of fever) before the commencement of antibiotic treatment, no significant difference in the rates of scarring on DMSA scans obtained 12 months later was evident (Table 1). Furthermore, given the widespread belief that infants and younger children are at increased risk, a separate analysis of patients between 1 month and 2 years of age yielded similar results, with no significant difference related to delay in treatment. The overall rates of scarring for the various age groups also were independent of the timing of treatment (Table 2).
The clinical and laboratory indices of inflammation support similar levels of severity of pyelonephritis in all groups (Table 3). Only the erythrocyte sedimentation rate showed a significant increase with duration of illness (P = .02); the C-reactive protein levels were consistently elevated and showed no significant change related to duration of fever. These results provide additional evidence of delayed treatment in the different groups. C-reactive protein is an acute-phase reactant that has a short half-life (19 hours), increasing early after the onset of inflammation and decreasing rapidly after its resolution. The erythrocyte sedimentation rate peaks much less rapidly and may take several days to decrease, even when the inflammation has been ameliorated.26,27
The benefits demonstrated after the initiation of antibiotic treatment were the eradication of infection in all cases and the time to resolution of fever, which remained relatively constant in all groups (1.6 ± 0.1 days) (Table 1). No significant difference in the incidence of scarring was seen in relation to the selection and route of administration of antibiotics.9 Given these findings, we recommend prompt treatment of febrile UTIs to facilitate rapid recovery from the acute illness, although we emphasize that we did not find early antibiotic treatment to be effective in reducing subsequent renal damage. This should allow a significant reduction in the sense of urgency and consequent anxiety experienced by the family in the event of suspected relapses or subsequent acute febrile episodes. It is a common experience of those who care for young children with UTIs to see the parents rush to the emergency department or their doctor within hours after the onset of fever, having received the advice that early treatment of relapsing pyelonephritis is essential to avoid renal damage. We think it is possible to advise a less-urgent approach for children with fever who appear otherwise well, even if there is a risk of recurrent UTI.
Numerous studies have addressed the treatment of acute pyelonephritis in children, comparing different antibiotics and different modes and durations of administration. In virtually all of those studies, the outcomes in terms of kidney damage are similar in the various arms, leading to the assumption that all treatments are equally effective in reducing scarring secondary to acute pyelonephritis, which occurs in 
30% of cases.
A limitation of this study is not knowing the exact time of the onset of infection. The closest we were able to come was to document accurately the onset of symptoms, with additional evidence provided by the time course of the acute-phase reactants.
Despite these limitations, this study reflects accurately the clinical situation in which a child presents as febrile and unwell, with symptoms suggesting acute pyelonephritis. At such a time, with the inflammatory process well established, it seems that antibiotics do little to reduce scarring. Additional research is needed to explore other avenues of therapy, such as the use of steroids or other antiinflammatory agents, and to evaluate the role of genetic factors that may predispose patients to scar formation.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Early treatment of acute pyelonephritis in infants and young children had no significant effect on the incidence of subsequent renal scarring. Furthermore, there was no significant difference in the rate of scarring after acute pyelonephritis when infants and young children were compared with older children.
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ACKNOWLEDGMENTS |
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Funding was provided by the Region of Veneto (research project 40/01) and the Association Il Sogno di Stefano (Stephen's Dream).
Participants in IRIS 1 and 2 were as follows: I. Marella, A. Budini (Adria); L. Marcazzò, S. Bellato (Arzignano); G. Audino, G. Picco (Bassano); P. Colleselli, D. Scorrano (Belluno); L. Pavanello (Castelfranco); C. Crivellaro (Chioggia); G. Cattarozzi, M. Pitter, A. Ballan (Dolo/Mirano); F. Rossetti, V. Cannella (Este/Monselice); G. Svaluto-Moreolo, V. Caddia (Feltre); G. Pozzan, F. Maschio (Mestre); P. Brisotto, N. Crema, S. Breseghella (Montebelluna); P. Luxardo, A. Toffolo (Oderzo); G. Zacchello, G. Montini, L. Murer, C. Carasi, B. Andreetta, S. Comacchio, L. Rigon, S. Sartori, L. Tomasi, R. Pertile, D. Gobber (epidemiologist), A. Ponzoni (statistician) (Padua); A. Truini (Piove di Sacco); P. G. Flora, M. Ranieri (San Donà); R. Dall'Amico, L. Donello (Thiene); G. Marcer, S. Zanchetta (Soave); M. Del Majno, M. Gheno (Venice); P. Biban, P. Fortunati (Verona-Borgo Trento); M. G. Santangelo, O. Gianesini (Vicenza); A. Corsini (Bentivoglio); P. P. Molinari (Bologna); A. Zucchini (Faenza/Lugo); A. Venturolli (Forlì); L. Serra (Imola); L. Casadio (Ravenna); M. Principi (Macerata); M. Pitschiller, W. Cassar (Bolzano); M. De Marini, G. Crescenzi (Cuneo).
We thank all of the members of the IRIS group who made the performance of this study possible, and we also thank Dr Andrea Ponzoni for statistical analysis. We particularly thank Dr Daniela Gobber (epidemiologist), who unfortunately passed away 2 years ago.
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FOOTNOTES |
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Accepted Dec 4, 2007.
Address correspondence to Giovanni Montini, MD, Nephrology, Dialysis, and Transplant Unit, Pediatric Department, Azienda Ospedaliera di Padova, Via Giustiniani, 3, 35128 Padova, Italy. E-mail: montini{at}pediatria.unipd.it
Both study protocols, IRIS 1 NCT00161330 and IRIS 2 NCT00156546, have been registered at www.clinicaltrials.gov.
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject Renal scarring is a frequent outcome of acute pyelonephritis in children. The American Academy of Pediatrics expressed concern regarding any delay in the treatment of febrile UTIs, supporting the concept that such delay increases the subsequent risk of kidney damage.
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| What This Study Adds Early treatment of acute pyelonephritis in infants and young children had no significant effect on the incidence of subsequent renal scarring. Furthermore, no difference in scarring rates was observed when infants and young children were compared with older children.
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