PEDIATRICS Vol. 121 No. 6 June 2008, pp. e1489-e1494 (doi:10.1542/peds.2007-2652)
ARTICLE |
Is Antibiotic Prophylaxis in Children With Vesicoureteral Reflux Effective in Preventing Pyelonephritis and Renal Scars? A Randomized, Controlled Trial
a Department of Pediatrics, Institute of Child Health IRCCS Burlo Garofolo, Trieste, Italy
c Unit of Epidemiology and Biostatistics, Institute of Child Health IRCCS Burlo Garofolo, Trieste, Italy
d Unit for Health Services Research and International Health, Institute of Child Health IRCCS Burlo Garofolo, Trieste, Italy
b Department of Pediatrics, "S. Maria degli Angeli" Hospital, Pordenone, Italy
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVES. There has been intense discussion on the effectiveness of continuous antibiotic prophylaxis for children with vesicoureteral reflux, and randomized, controlled trials are still needed to determine the effectiveness of long-term antibiotics for the prevention of acute pyelonephritis. In this multicenter, open-label, randomized, controlled trial, we tested the effectiveness of antibiotic prophylaxis in preventing recurrence of pyelonephritis and avoiding new scars in a sample of children who were younger than 30 months and vesicoureteral reflux.
METHODS. One hundred patients with vesicoureteral reflux (grade II, III, or IV) diagnosed with cystourethrography after a first episode of acute pyelonephritis were randomly assigned to receive antibiotic prophylaxis with sulfamethoxazole/trimethoprim or not for 2 years. The main outcome of the study was the recurrence of pyelonephritis during a follow-up period of 4 years. During follow-up, the patients were evaluated through repeated cystourethrographies, renal ultrasounds, and dimercaptosuccinic acid scans.
RESULTS. The baseline characteristics in the 2 study groups were similar. There were no differences in the risk for having at least 1 pyelonephritis episode between the intervention and control groups. At the end of follow-up, the presence of renal scars was the same in children with and without antibiotic prophylaxis.
CONCLUSIONS. Continuous antibiotic prophylaxis was ineffective in reducing the rate of pyelonephritis recurrence and the incidence of renal damage in children who were younger than 30 months and had vesicoureteral reflux grades II through IV.
Key Words: vesicoureteral reflux • antibiotic prophylaxis • pyelonephritis • renal scars
Abbreviations: VUR—vesicoureteral reflux • RCT—randomized, controlled trial • UTI—urinary tract infection • DMSA—dimercaptosuccinic acid • RR—relative risk • CI—confidence interval
In recent years, the effectiveness of continuous antibiotic prophylaxis in children with vesicoureteral reflux (VUR) has been intensely discussed.1–7 The question is not only whether antibiotics are effective in preventing recurrent acute pyelonephritis but also whether they modify the natural history of disease and help to prevent the appearance of new kidneys scars. The evidence on the effectiveness of antibiotic prophylaxis on both outcomes is scanty: the randomized, controlled trials (RCTs) published so far are poorly designed and conducted in very heterogeneous populations of children (ie, spanning from 6 months to 14–18 years of age and pooling patients with and without VUR).5 A recently updated Cochrane Systematic Review confirmed heterogeneity and poor quality of studies on this topic. The authors suggested that high-quality RCTs are needed to determine the effectiveness of long-term antibiotics for the prevention of urinary tract infections (UTI) in susceptible children.3 Moreover, the presence of VUR has not been firmly shown to be a risk factor for recurrence of pyelonephritis, and a direct association between VUR and the presence of scars or the appearance of new scars has not been demonstrated. The only available evidence is of an association, almost exclusively confined to male infants, between VUR of grades IV to V and prenatal renal dysplasia.8
Despite the lack of evidence, some practice guidelines and studies recommended long-term antibiotic prophylaxis for children with any degree of VUR.9–11 The objective of this study was to assess the effectiveness of antibiotic prophylaxis in preventing pyelonephritis and in avoiding the occurrence of new scars in children who were younger than 30 months and had VUR.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Study Setting
This open-label, multicenter, RCT was conducted in 7 pediatric hospital units in northern Italy: Trieste, Pordenone, Monfalcone, San Daniele, Tolmezzo, Cesena, and Bologna. The study was approved by the Technical Scientific Committee of the coordinating Centre (Institute of Child Health Burlo Garofolo, Trieste) and by the local ethics committee (Prot. CE/V-68). Written informed consent was obtained for all patients. Enrollment started in November 1999 and ended in March 2003.
Study Outcomes
The primary outcome was the recurrence of pyelonephritis. The secondary study outcome was the progression of renal damage, defined by the appearance of new scars or worsening in dimercaptosuccinic acid (DMSA) uptake.
Inclusion Criteria
The inclusion criteria were the presence of VUR grade II, III, or IV,12 monolateral or bilateral, diagnosed between 1 day and 30 months of age at the first episode of acute pyelonephritis. Acute pyelonephritis was defined by fever of unknown origin (rectal temperature > 38.5°C), positive result of urinalysis (presence of leukocytes and bacteria at optical microscopy), and positive results of urine culture (
1 million colony-forming units/mL) for the same bacterium in 2 different samples. Urine for urinalysis and urine culture was collected using clean catch and bladder catheterization in case of septic patient. Exclusion criteria were the presence of previous episodes of pyelonephritis, even if only suspected (eg, an episode of fever treated with antibiotics without performing urine culture); VUR grade I, because of the high probability of rapid spontaneous resolution13; VUR grade V, concerned by the high incidence of associated renal dysplasia; or recurrence of acute pyelonephritis before the first DMSA renal scan, if this was positive for scars.
Study Design and Intervention
A centralized randomization was conducted using a computerized minimization procedure (Minimization Software, Michael Conlon, Division of Biostatistics, Department of Statistics, University of Florida, May 1991) to balance for gender, age group (0–3, 4–11, 12–23, and 24–30 months), and VUR grade.14 When a patient was identified for enrollment, the person in charge in each study site called the epidemiologist at the coordinating center (Institute of Child Health, Burlo Garofolo, Trieste, Italy) who conducted the assignment procedure on the basis of gender, age, and VUR grade. When a patient had bilateral VUR, the highest grade of reflux present was used for categorization. Children were randomly assigned to 1 of 2 groups:
- an intervention group (children who were assigned to the intervention group received antibiotic prophylaxis with sulfamethoxazole/trimethoprim [1–2 mg/kg trimethoprim and 5–10 mg/kg sulfamethoxazole once daily]; in case of intolerance (leucopoenia) or for children who were younger than 6 months, nitrofurantoin [2 mg/kg once daily] was planned but never used); or
- a control group (children who were assigned to the control group did not receive antibiotic prophylaxis).
Evaluators and study patients were not blinded to the treatment assigned.
At entry into the study, each patient underwent cystourethrography, performed 2 months after the acute episode. A renal ultrasound was also performed. Moreover, all children underwent DMSA renal scan 6 months after the acute episode of pyelonephritis. 99mTC-dimercaptosuccinic acid was given in a dosage of 0.5 MBq/kg body weight (minimum 10 MBq); image acquisition (6 projections + Single Photon Emission Computerized Tomography [SPECT]) was performed at least 3 hours after injection. DMSA scans were considered abnormal when 1 area of decreased DMSA uptake had been pointed out (suggesting the presence of renal scars), with or without preservation of the renal outline, paying attention to avoiding to consider central defects located over the pelvicalyceal system as abnormal. Separate renal function <45% with or without focal defects was considered abnormal. The radiologists who performed renal ultrasounds, cystourethrography, and DMSA renal scan were blinded to whether the patients were in the study.
At each episode of fever that occurred after enrollment or when symptoms of UTI occurred (eg, change in the smell of urine, anorexia, irritability), urinalysis and urine culture were performed to confirm the presence of pyelonephritis. Pediatricians in each study site, after consulting with the research coordinator, prescribed antibiotic treatment (oral ceftibuten, cefaclor, or amoxicillin/clavulanate for 10 days) to children with recurrence of pyelonephritis. The treatment was changed on the basis of the performed antibiogram when the bacterium involved was resistant to the started therapy.
Follow-up
Two years after enrollment, the patients who were assigned to antibiotic prophylaxis stopped taking antibiotics even when the VUR persisted; patients who were assigned to the control group continued without antibiotic prophylaxis. All patients were followed up for an additional 2 years, for a total follow-up of 4 years. At the end of the second year of follow-up, all children underwent cystourethrography again and renal ultrasound. All children with persistent VUR underwent a third cystourethrography after 4 years. DMSA renal scan was repeated after 2 years when the first DMSA was abnormal (uptake decreased and/or evidence of scar),15 when patients had a pyelonephritis recurrence during follow-up after a normal DMSA, and for all the children with abnormal renal ultrasounds (focal defects or decreased longitudinal maximum renal diameter).16 For children with recurrence of pyelonephritis, the presence of antibiotic in the urine was tested to assess the compliance with assigned treatment.
Sample Size
To determine the sample size, we used the results of previous RCTs.17–19 We estimated a 30% risk for recurrence for children who received antibiotic prophylaxis and a 60% risk for those who did not receive it. We calculated that 48 patients were needed in each study group to identify a 30% risk for recurrence in the prophylaxis group and a 60% risk in the control group (ie, an absolute 30% risk difference) with 95% precision and 80% power.
Statistical Analysis
Data were analyzed on an intention-to-treat basis. Continuous data were summarized as means and SD and categorical data as numbers, percentages, relative risks (RR), and related 95% confidence intervals (CIs). Differences between continuous variables were assessed with analysis of variance. 
2 test was used to analyze categorical data. Statistical analysis was conducted with SPSS 9.0 (SPSS Inc, Chicago, IL). P < .05 was considered statistically significant in the analysis.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Figure 1 shows the study algorithm. A total of 124 white patients were eligible to be included in the study. Of these, the parents of 24 refused their participation. Patients were comparable for gender, age, and grade of VUR to the enrolled patients. One hundred (81%) patients were randomly assigned: 50 to antibiotic prophylaxis and 50 to the control group. Independent of the instructions that they received, 6 patients who were assigned to antibiotic prophylaxis did not take the prescribed treatment; 4 patients who were assigned to the control group took antibiotic prophylaxis. The analysis was conducted by intention-to-treat. There was no loss to follow-up.
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The characteristics of the 100 patients who were randomly assigned are shown in Table 1. Baseline characteristics were similar between the 2 groups. The randomization procedure perfectly balanced the groups in terms of age (>60% were younger than 1 year, and 30% were between 12 and 24 months of age), gender, and grade of VUR. The clinical differences (DMSA scan and the presence of scars) were not clinically relevant.
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Thirty-3 (33%) children presented at least 1 pyelonephritis recurrence in the first 2 years of follow-up, 18 (36%) in the intervention group and 15 (30%) in the control group. The total number of recurrences was 42 and 35, respectively. The risk for having at least 1 pyelonephritis recurrence was slightly higher but not statistically significant in the intervention than in the control group (RR: 1.2 [95% CI: 0.68–2.11]). The rates of pyelonephritis recurrence and mean number of episodes during the first 2 years of follow-up are shown in Table 2. In the first year after enrollment, the RR for having at least a recurrence in patients with antibiotic prophylaxis versus those without was 1.42 (95% CI: 0.76–2.65); the RR in the second year of follow-up was 1.25 (95% CI: 0.54–2.90); in neither case was the difference statistically significant. There were not differences in VUR grade between children with at least 1 recurrence in the first 2 years of follow-up: among the 18 children in the prophylaxis group, there was 1 patient with VUR grade II, 9 with VUR grade III (3 of them bilateral), and 8 with VUR grade IV (2 bilateral). In the nonprophylaxis group, 7 of 15 had VUR grade III (4 bilateral) and 8 VUR grade IV (5 bilateral). The male:female ratio was 7:11 for children with recurrence in the intervention group and 6:9 in the control group.
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In the subsequent 2 years of follow-up, when antibiotic prophylaxis in the intervention group was discontinued, only 3 patients developed pyelonephritis: 1 in the intervention group and 2 in the control group. The recurrences in the prophylaxis group were caused by multiresistant bacteria: Escherichia coli in 37 cases, Pseudomonas aeruginosa in 3, Enterococcus fecalis in 2, Morganella morganii in 1. All E coli were resistant to sulfamethoxazole/trimethoprim, 12 also to amoxicillin; all were sensitive to cephalosporins and ciprofloxacin. The 3 Pseudomonas aeruginosa were resistant to sulfamethoxazole/trimethoprim, ampicillin, and amoxicillin and sensitive to ciprofloxacin, aminoglycosides, and ceftazidime. All E fecalis were resistant to sulfamethoxazole/trimethoprim and sensitive to ampicillin and amoxicillin. M morganii was resistant to sulfamethoxazole/trimethoprim, amoxicillin with or without clavulanate, and ampicillin and sensitive to aminoglycosides and ciprofloxacin.
In the control group, all the recurrences were caused by E coli sensitive to all of the antibiotics tested in the antibiogram. The test for the presence of antibiotic in the urine of children with recurrences was positive in patients who were taking prophylaxis and negative in those who were not taking it. None of the 10 children (6 patients assigned to antibiotic prophylaxis and 4 patients assigned to the control group) who did not comply with the assigned treatment (Fig 1), had a recurrence.
A persistent VUR was present in 31 (62%) patients in the intervention group and 40 (80%) in the control group (P = .05) after the first 2 years of follow-up. Twenty-six (52%) patients in the intervention and 25 (50%) in the control group (P = .8) showed a persistent VUR at the end of the 4-year follow-up. There were not differences between groups in VUR grade: 3 patients in each group had VUR grade IV at the end of the follow-up; 13 and 14 patients, respectively, VUR grade III; 10 and 8, respectively, VUR grade II or I (Table 3).
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None of the children with VUR grade II had an abnormal DMSA at entry; 14 (30%) of 46 with VUR grade III and 22 (67%) of 33 with VUR grade IV had an abnormal DMSA scan. At the end of the 4-year follow-up, a worse DMSA was detected for 10 patients, all grade IV: 6 worsened without any recurrence, and 3 worsened with 1 or 2 episodes of pyelonephritis; only 1 case, in the intervention group, worsened with 6 recurrences. For 26 children with
1 recurrence, there was no worsening at DMSA. Among the 6 patients with the largest number of recurrences (4–6), 5 showed an unmodified renal DMSA scan and only 1 showed a worsening DMSA; a severe dysplasia was previously present, however, in this patient, and she was in the intervention group. DMSA uptake and rate of renal scars after the first 2 years of follow-up are shown in Table 4. There were no statistically significant differences between groups. The presence of renal scars was the same in children with or without antibiotic prophylaxis (RR: 1.22 [95% CI: 0.75–1.98]). Moreover, there were no patients with new renal damage during the whole follow-up period.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This multicenter, RCT showed that antibiotic prophylaxis is ineffective in preventing pyelonephritis recurrences and renal damage. We enrolled a homogeneous population of children who were younger than 30 months, all with VUR at first episode of pyelonephritis. Sixty percent of these children were younger than 1 year, >30% had VUR grade IV, half of them bilateral, and we followed them up for the 2 years of prophylaxis and for an additional 2 years afterward. Our study was open label and unblinded. The risk for bias attributed to lack of blinding was limited by the use of objective criteria—urine culture and DMSA scan—to define the main outcomes (relapses and renal damage). The radiologist who performed the DMSA scan and the operator who analyzed the urine culture both were blinded on patients' allocation. Moreover, compliance with the assigned prescription (prophylaxis or not) was assessed by testing for antibiotic activity in the urine at the time of recurrence of pyelonephritis. The sample size of our study was calculated on the hypothesis that antibiotic prophylaxis offered an advantage over nonprophylaxis, as reported by previous literature,17–19 and is underpowered to exclude the existence of a difference between the 2 groups; however, given the observed trend in favor of the control group with respect to the main outcome variable, the likelihood of the opposite result is low.
Our findings do not support the view that VUR predisposes to pyelonephritis and that pyelonephritis can be the cause of progressive damage to renal parenchyma.20 A high proportion of chronic renal failure in children and young adults has been attributed to this causal pathway, also known as "reflux nephropathy,"21,22 For this reason, several practice guidelines emphasize the need for early detection of VUR by using micturating cystourethrography and renal ultrasounds after a first episode of pyelonephritis in all children who were younger than 2 years.9–11 In the 1980s, several studies showed that surgical treatment is ineffective in preventing renal damage and its progression in children with different grades of VUR.23–25 All of these trials compared surgery and long-term antibiotic prophylaxis. None of the studies considered a "no-intervention" arm.26 Continuous antibiotic prophylaxis is still recommended for children with VUR of any degree.5,11 Actually, the analysis of the main database on chronic renal failure shows that the introduction of an aggressive surgical and/or medical treatment policy, applied for children with VUR since the 1960s, has not been associated with a decreased incidence of the final stage of renal failure caused by reflux nephropathy.2,27
Recently, improvements in prenatal diagnosis have drawn attention to the association between renal dysplasia and VUR as cause of chronic renal failure. Renal dysplasia with grade IV/V of VUR, typical of male children, has its own natural progression independent of pyelonephritis recurrences; this may explain the stable incidence of chronic renal failure in years of aggressive treatment policies.8,28,29 After a single episode of pyelonephritis, the risk for developing chronic renal failure is <1 in 1 million,30 and early detection of VUR is useful only when antibiotic prophylaxis is effective in reducing the rate of pyelonephritis recurrences and scar lesions.4 So, should we really prescribe antibiotic prophylaxis to all of these children? Our results are in accordance with a recent RCT6 and cohort study,7 both concluding that there is no evidence of effectiveness for long-term antibiotic prophylaxis in preventing pyelonephritis recurrences or the occurrence of renal scars. The recently updated (May 2006) Cochrane Systematic Review on long-term antibiotics for preventing recurrent urinary tract infection in children concluded that the small number of poor-quality studies give no reliable evidence of the effectiveness of antibiotics in preventing recurrent symptomatic UTI.3
As far as renal damage is concerned, it seems to be correlated with the presence of dysplasia and not to recurrences of pyelonephritis.8,28,29 In our study population, DMSA demonstrated a progression of the disease without pyelonephritis recurrence. In effect, none of the patients with VUR grade II had an abnormal DMSA scan, whereas 30% of patients with grade III and 67% of patients with grade IV showed an abnormal DMSA scan at enrollment. These are the same percentages found in series of children with prenatal diagnosis of VUR with associated renal dysplasia.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Continuous antibiotic prophylaxis is not effective in reducing the rate of infection and the incidence of renal damage and its progression, which seems to be associated with the presence of VUR and its grade. Early and correct diagnosis and prompt treatment of episodes remain the pillars of correct case management of pyelonephritis and should be emphasized in practice guidelines.
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ACKNOWLEDGMENTS |
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This study was funded by the Italian Ministry of Health (research grant 35/00). The sponsor had no role in design, data collection, analysis and interpretation, or reporting of this study.
Members of the North East Italy Prophylaxis in VUR study group included Tiziano Basso (Tolmezzo), Cantoni Luigi (San Daniele), Montanari Paolo (Bologna), Marcella Montico (Trieste), Olivo Gigliola (Monfalcone), and Pocecco Mauro (Cesena).
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FOOTNOTES |
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Accepted Nov 30, 2007.
Address correspondence to Marco Pennesi, MD, Clinica Pediatrica, Istituto per l'Infanzia IRCCS Burlo Garofolo, Via dell'Istria 65/1, 34100 Trieste, Italy. E-mail: pennesi{at}burlo.trieste.it
This trial has been registered at www.clinicaltrials.gov (identifier NCT00382343).
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject For children with VUR, the effectiveness of continuous antibiotic prophylaxis for the prevention of acute pyelonephritis and the hypothesized consequent renal damage has not yet been proven by well-designed randomized, controlled trials.
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| What This Study Adds This multicenter, open-label, randomized, controlled trial demonstrates that continuous antibiotic prophylaxis is ineffective in reducing the rate of pyelonephritis recurrence and the incidence of renal damage in children who are younger than 30 months and have VUR grades II through IV.
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