► Introduction
Febrile urinary tract infection (UTI) is a common bacterial infection in young children, 1 with 19% evidence of renal scarring in late follow-up with Tc 99m dimercaptosuccinic acid (DMSA) scan (scintigraphy). 2
Although the prognosis of a single episode of febrile UTI is usually good, the main concerns are related to the possible long-term effects on renal function secondary to the development of renal scarring.
Long-term antibiotic prophylaxis has been proposed to reduce the incidence of UTI with the intention of reducing related renal scarring; However, it is not without costs and risks. The purpose of this systematic review is to determine whether those costs and risks could be offset by a benefit in reducing permanent kidney damage in the form of pyelonephritic scars.
The authors do not agree that prevention of a single symptomatic or febrile UTI in the absence of a significant reduction in healing warrants up to 16 years of continuous antibiotic prophylaxis per patient 3 along with reconsideration of the need for invasive radiological investigation to determine if the vesicoureteral reflux has resolved.4 Most of the published studies on antibiotic prophylaxis have focused on reducing the number of UTIs, although the most appropriate substitute criterion to evaluate long-term efficacy based on renal function is the prevention of post-infectious renal scars, which represent the most important adverse outcome from the patient’s perspective.
Therefore, we performed the present systematic literature review and meta-analysis to explore the role of antibiotic prophylaxis as a preventive measure in the onset and worsening of renal scarring in children after symptomatic or febrile UTI. , as no single study to date has shown differences in healing rates as a primary outcome.
► Methods
The meta-analysis was conducted and reported according to the preferred reporting items for systematic reviews and meta-analysis guidelines5; however, it was not registered on a website. We searched Medline (1946 to August 2016), Embase (1980 to August 2016) and the Cochrane Controlled Trials Register for studies reporting on UTI, with reporting limited to children (≤ 18 years of age) who were to be randomized in a study involving the use of prophylactic antibiotics.
Children had to be prospectively randomized to a treatment group (antibiotic prophylaxis) or a control group (no treatment or placebo). The electronic search was complemented by a search of the bibliographies of the included articles. A requirement for the detection of renal scarring was the need to perform a technetium DMSA scan at baseline with a delayed scan at 12 months to 2 years to document any scarring. The DMSA scan report in the studies was extracted manually, as they were not reliably documented in the Medical Subject Headings of the electronically retrieved references.
The DMSA scan at baseline was necessary for the detection of renal parenchymal involvement of the UTI with a photon-deficient area, or previous scars, where, in addition to a photon-deficient area, contraction and distortion of the renal cortex with loss of volume is often seen. Delayed DMSA scanning was necessary to detect new scarring and determine whether the intervention (antibiotic prophylaxis) led to a reduction in renal parenchymal damage. The search was carried out without excluding the base language in the publication.
Study selection was performed by two independent reviewers (IKH and MP) based on titles and abstracts. The full text of documents that appeared to meet the selection criteria was reviewed. Disagreement in full-text selection and review was resolved by consensus. The outcome of the review was the presence of new scar formation or worsening of existing scars as determined by the DMSA scan.
♦ Statistical methods
A Mantel-Haenszel fixed-effects meta-analysis was performed, pooling data across studies to test the effectiveness of the intervention (continuous antibiotic prophylaxis) versus controls (placebo or no treatment) on the risk of new scars or worsening of existing scars.
Descriptive statistical analyzes were performed using risk ratios (RR) and 95% confidence intervals (CI) as appropriate. Heterogeneity among the included studies was assessed.
A subgroup analysis was performed that was restricted to children with VUR. Statistics were performed using Review Manager version 5.3 (Nordic Cochrane Center, Cochrane Collaboration, Copenhagen, Denmark).
► Risk of bias
Bias assessment was performed independently by 2 study authors (IKH, MP) according to the Cochrane Collaborative checklist.
Differences were resolved through discussion. Funnel plots were used to detect evidence of publication bias. A subgroup analysis was performed for those children with VUR, with repeated bias assessment.
► Results
♦ Search results
A total of 1398 studies were identified using the search criteria. After electronic removal of duplicates and screening of titles and abstracts, 189 potentially relevant studies were identified for full review. A detailed analysis of these studies was performed, including a full-text review when an article could meet the selection criteria.
Studies published in languages other than English were translated by study authors who were fluent in the language, and recourse to institutional translation staff was unnecessary. The search was carried out at www.clinicaltrial .
The government database (26 studies identified) did not find any additional randomized controlled trials (RCTs). Seven published studies met all inclusion criteria in the meta-analysis and were selected for the final review.
♦ Description of excluded studies
The general search terms were designed to capture all possible relevant studies. The most common articles excluded were comments and reviews containing the search terms, duplicate articles reporting on different aspects of the same studies, studies of different antibiotic agents, studies of adults, and prospective studies often comparing different antibiotics or antibiotics versus surgical intervention without a control or placebo or any treatment group. Three studies addressed prenatal hydronephrosis without prior UTI. One study was reported abstractly at a meeting as initiated; however, a search of the authors and title did not reveal published results.
♦ Description of included studies
All studies included in this meta-analysis were prospective RCTs. Seven RCTs3,7-12 (1427 subjects) were included in the meta-analysis on the effect of antibiotic prophylaxis on UTI-related renal scar. A subgroup meta-analysis was conducted on the included studies, restricting the population to those with documented VUR (1076 subjects) to determine whether prophylaxis proved to be beneficial in this population at increased risk for UTI.
♦ Risk of bias in included studies
The risk of bias graph demonstrates that the main bias is lack of adequate blinding. Four studies 7 - 9, 11 provided no treatment in the control arm, while only 3 studies 3, 10, 12 provided a placebo. For all selected studies, scar was a secondary outcome. The primary outcome was always symptomatic or febrile recurrence of UTI. One study10 left the performance and timing of DMSA scans for scar detection to the discretion of the treating physician, introducing bias in terms of selection for investigation of scar formation. In several studies, the method of random sequence generation or the method of allocation concealment was not clearly identified. 7, 11 In one study, attrition and risk of bias at presentation were possible.7 None of the studies reported loss to follow-up > 10% in either arm.
♦ Effectiveness of Interventions
Seven RCTs 3, 7 - 12 (1427 subjects) were included in the meta-analysis, with 6 RCTs 3, 7 - 9, 11, 12 (1004 subjects) included in the meta-analysis subgroup restricted to those with VUR. Both meta-analyses showed no difference in the incidence of scar formation between the groups with and without prophylaxis (pooled RR, 0.83; 95% CI, 0.55-1.26 [renal scar in all subjects]; RR , 0.82; 95% CI: 0.51-1.31 [scar restricted to subjects with UVR]). Re-healing was observed in 5.7% of all children and 6.3% of those with VUR. There was no significant heterogeneity. Funnel plots demonstrated no evidence of publication bias.
► Discussion
The attention of pediatricians and researchers studying UTI as a risk factor for kidney damage has focused on the risk of UTI recurrence, rather than the risk of scarring, as a surrogate endpoint for long-term kidney function. term. In this regard, almost all RCTs conducted with antibiotic prophylaxis have assumed that a reduction in recurrent infection rates would result in a significant reduction in healing. To date, no trial has shown any benefit with respect to reducing UTI-related kidney scarring, apart from the Swedish reflux study.11 In this trial of children with dilant VUR, girls in the control surveillance group were compared with the antibiotic prophylaxis group, demonstrating a significant increase in new kidney damage.
Because to date no RCT has been designed or powered primarily to assess the risk of scarring, a systematic review and meta-analysis was performed to further explore the potential influence of antibiotic prophylaxis on scarring. In the >1400 children (mostly girls) studied who presented with febrile or symptomatic UTI, there was no significant influence of antibiotic prophylaxis in preventing scarring, as demonstrated by the meta-analysis.
The same occurs with the subgroup analysis restricted to the 1076 children with VUR. Furthermore, the risk of developing new scars was low, ~6%, in the population considered, with the vast majority of kidneys evaluated being normal at presentation and at the end of follow-up. This indicates that the majority of children with a first symptomatic or febrile UTI have normal kidneys (as exemplified by the Randomized Intervention for Children with Vesicoureteral Reflux study, 3 where 96.4% of the 582 children had normal kidneys). at the time of enrollment) and are not at risk for long-term adverse outcomes.
The reduction in febrile UTIs has been minimal, with the largest study 3 requiring 16 to 22 years of antibiotic treatment to prevent a symptomatic or febrile UTI, respectively. Given that 19% of febrile urinary tract infections result in scarring2, any clinical benefit of prophylaxis is negligible. This lack of influence on healing is also confirmed by the present meta-analysis, which did not demonstrate any benefit, despite the fact that the combined studies document 1068 patients/year with antibiotic prophylaxis.
Furthermore, the results of these meta-analyses support the current surveillance approach of published guidelines for the investigation and management of first febrile UTIs in infants and young children.13-17 They do not advocate routine antibiotic prophylaxis. The American Academy of Pediatrics, in particular, reconsidered its UTI guidelines in light of the randomized intervention for children with VUR, the largest trial on this topic, and reaffirms the 2011 recommendations. 18
Data from international end-stage renal disease (ESRD) registries 19 - 22 show that the population at serious risk of chronic kidney damage are those children, predominantly boys, with significant congenital anomalies of the kidney and urinary tract. (CAKUT- congenital abnormalities of the kidney and urinary tract), particularly hypodysplasia, while the risk of ESRD after UTI in healthy children remains anecdotal. CAKUTs are the primary cause of ESRD and renal replacement therapy (dialysis or transplant) in children22, and are now detected on prenatal ultrasound.
Unfortunately, to the best of our knowledge, no prospective randomized studies have been conducted on this specific population. It is recognized that the rate at which hypodysplastic kidneys decline in function is slow 20, 22; Interventions that could slow the progression of chronic kidney disease in this population of children, including antibiotic prophylaxis, have not been prospectively evaluated. Furthermore, much more needs to be understood about the genetic determinants of CAKUT, particularly hypodysplasia and propensity for scarring.
Limitations of this meta-analysis relate to healing being a secondary rather than primary outcome in all studies, the lack of blinding and placebo in most studies, the age range of the populations studied vary considerably, and a disproportionate proportion of girls in several studies. The strengths of this meta-analysis relate to the search restricted to prospective RCTs with a well-defined objective: renal healing.
This is an exciting and challenging time when it is no longer necessary, nor justified, to over-research and treat the vast majority of healthy children who have an uncomplicated UTI, but rather to focus on the infants and children who are destined to experience chronic kidney disease to determine by what means your suffering can be alleviated. In children with or without VUR and normal kidneys, the absence of any static benefit in reducing renal scarring does not justify the possible side effects of long-term exposure to antibiotics.
